Isophthalic acid derivatives

ABSTRACT

The present invention relates to isophthalic acid derivatives, to a process for their preparation and to their use for producing medicaments for the treatment and/or prophylaxis of diseases in humans and animals, in particular of cardiovascular disorders.

The present invention relates to isophthalic acid derivatives, to aprocess for their preparation and to their use for producing medicamentsfor the treatment and/or prophylaxis of diseases in humans and animals,in particular of cardiovascular disorders.

Cysteinyl-leukotrienes are important mediators for a large number ofpathological disease states. They are formed from arachidonic acid onactivation of inflammatory cells such as, for example, polymorphonuclearleukocytes, macrophages and mast cells, with the aid of 5-lipoxygenase.This involves initial production of leukotriene A4 (LTA4) which is thenconverted in further reaction steps by addition of glutathione intoleukotriene C4 (LTC4). Further metabolism then results in leukotriene D4(LTD4) and leukotriene E4 (LTE4). LTC4, LTD4 and LTE4 are referred tocollectively as cysteinyl-leukotrienes.

The physiological effect of cysteinyl-leukotrienes are mediated via Gprotein-coupled receptors. Two cysteinyl-leukotriene receptors have beenpharmacologically and molecular-biologically characterized:

Cysteinyl-leukotriene receptor 1 (CysLT1) is activated chiefly by LTD4,but also, more weakly, by LTC4 and LTE4. It is therefore also referredto as the LTD4 receptor. Cloning and characterization of the receptorwere possible in 1999 (Lynch et. al. (1999) Nature 399; 789-793). TheCysLT1 receptor shows strong expression in the spleen, peripheralleukocytes and lungs. Expression of the CysLT1 receptor in the humanheart has not to date been detectable. CysLT1-specific receptorantagonists such as, for example, pranlukast, zafirlukast andmontelukast lead to relaxation of the smooth muscles of the bronchi andhave been developed for the treatment of bronchial asthma.

Cysteinyl-leukotriene receptor 2 (CysLT2) is activated chiefly by LTC4,but also, more weakly, by LTD4 and LTE4. It is therefore also referredto as LTC4 receptor. Identification and characterization of the receptorwas possible in 2000 (Heise et. al. (2000) Journal of BiologicalChemistry 275; 30531-30536; Takasaki et. al. (2000) Biochem. Biophys.Res. Commun. 274; 316-322; Nothacker et. al. (2000) Mol. Pharmacol 58;1601-1608). The human CysLT2 receptor shows very strong expression inthe heart, placenta, spleen and peripheral blood leukocytes (PBL). Itwas possible to show with the aid of PCR investigations and in-situhybridzations that this receptor is expressed in the heart in smoothmuscle cells of coronary arteries, in myocytes and very strongly also inPurkinje fibres (Kamohara et. al. (2001) Biochem. Biophys. Res. Commun.287; 1088-1092; Hui et. al. (2001) Journal of Biological Chemistry 276;47489-47495). On activation of the CysLT2 receptor there is, as with theCysLT1 receptor, an increase in the intracellular calcium concentration.

Cysteinyl-leukotrienes are vasoactive substances, i.e. they lead to astrong constriction of coronary arteries. In addition, they reduce thecontractility of the heart, induce changes in the electrocardiogram,influence the blood pressure, increase the microovascular permeability,promote oedema formation and induce strong bronchoconstriction (Lettset. al. (1987) Cardiovasc. Clin. 18; 101-113; Fauler and Frölich (1989)Cardiovasc. Drugs and Therapy 3; 499-505; Piper et. al. (1990) Adv.Prostaglandin Thromboxane Leukotr. Res. 20; 146-152). Antagonists ofcysteinyl-leukotriene receptors therefore form one therapeutic approachto the treatment of cardiovascular disorders.

EP-A 516 069 describes leukotriene B4 antagonists for the treatment ofallergic and inflammatory disorders. EP-A 791 576 and EP-A 341 551disclose leukotriene antagonists for the treatment of asthma.

The present invention relates to compounds of the formula (I)

in which

-   A is a 4- to 7-membered nitrogen-containing saturated heterocycle    which is bonded via the nitrogen atom to the keto group and which    optionally has a carbonyl group adjacent to a nitrogen atom, or-   a radical

-    in which    -   E is (C₃-C₇)-cycloalkanediyl, (C₅-C₇)-cycloalkenediyl or is 5-        to 10-membered heterocyclyl which is bonded via a carbon atom to        the [CH₂]_(o) group,    -   o is 0, 1 or 2,    -   R³ is hydrogen or (C₁-C₆)-alkyl, and    -   * is the point of linkage to the keto group,-   m 0, 1 or 2,-   n is 1, 2, 3 or 4,-   R¹ is hydrogen or (C₁-C₆)-alkyl,-   R² is hydrogen or (C₁-C₆)-alkyl,-   X is a bond, —CH═CH—, —C≡C— or O,-   Y is O, *—NH—C(═O)— or NH,    -   in which    -   * is the point of linkage to the phenyl ring, and-   Z is located in the position meta or para to the substituent X and    is either (C₆-C₁₀)-alkoxy which may comprise 1 or 2 further oxygen    atoms in the chain, or-   a radical

-    in which    -   G is a bond, O or S,    -   L is (C₁-C₆)-alkanediyl, (C₃-C₆)-alkenediyl or        (C₃-C₆)-alkynediyl,    -   M is a bond, O or S,    -   R⁴ is (C₆-C₁₀)-aryl, biphenylyl, phenoxyphenyl, benzyloxyphenyl,        (E)-phenylvinylphenyl, 2-phenylethylphenyl, tetrahydronaphthyl,        benzyl, heteroaryl, 5- to 10-membered heterocyclyl,        (C₃-C₇)-cycloalkyl or (C₃-C₇)-cycloalkylmethyl, where aryl,        biphenylyl, phenoxyphenyl, benzyloxyphenyl,        (E)-phenylvinylphenyl, 2-phenylethylphenyl, tetrahydronaphthyl,        benzyl, heteroaryl, heterocyclyl, cycloalkyl and        cycloalkylmethyl in turn may be substituted up to three times        independently of one another by halogen, cyano, nitro,        trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl,        (C₁-C₆)-alkoxy, (C₂-C₆)-alkenyl, (C₃-C₇)-cycloalkyl,        (C₃-C₇)-cycloalkylmethoxy, (C₅-C₇)-cycloalkenyl,        (C₃-C₇)-cycloalkoxy or (C₅-C₇)-cycloalkenyloxy, and    -   * is the point of linkage to the phenyl ring,        and the salts, hydrates, hydrates of the salts and solvates        thereof.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, thecompounds of the formulae mentioned below which are encompassed byformula (I), and the salts, solvates and solvates of the salts thereof,and the compounds encompassed by formula (I) and mentioned below asexemplary embodiments, and the salts, solvates and solvates of the saltsthereof, insofar as the compounds encompassed by formula (I) andmentioned below are not already salts, solvates and solvates of thesalts.

The compounds of the invention may, depending on their stricture, existin stereoisomeric forms (enantiomers, diastereomers). The inventiontherefore relates to the enantiomers or diastereomers and respectivemixtures thereof. The stereoisomerically pure substituents can beisolated in a known manner from such mixtures of enantiomers- and/ordiastereomers.

Where the compounds of the invention can occur in tautomeric forms, thepresent invention encompasses all tautomeric forms.

Salts preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds of the invention.However, salts which are themselves unsuitable for pharmaceuticalapplications but can be used for example for isolating or purifying thecompounds of the invention are also encompassed.

Physiologically acceptable salts of the compounds of the inventioninclude acid addition salts of mineral acids, carboxylic acids andsulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid,sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonicacid, toluenesulphonic acid, benzenesulphonic acid,naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid,propionic acid, lactic acid, tartaric acid, malic acid, citric acid,fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds of the invention alsoinclude salts of conventional bases such as, for example and preferably,alkali metal salts (e.g. sodium and potassium salts), alkaline earthmetal salts (e.g. calcium and magnesium salts) and ammonium saltsderived from ammonia or organic amines having 1 to 16 C atoms, such as,for example and preferably, ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methyl-morpholine, arginine, lysine, ethylenediamineand N-methylpiperidine.

Solvates refer for the purposes of the invention to those forms of thecompounds of the invention which form a complex in the solid or liquidstate through coordination with solvent molecules. Hydrates are aspecific form of solvates in which the coordination takes place withwater.

For the purposes of the present invention, the substituents have, unlessspecified otherwise, the following meaning:

Alkyl per se and “alk” in alkoxy stand for a linear or branched alkylradical having usually 1 to 6, preferably 1 to 4, particularlypreferably 1 to 3, carbon atoms, by way of example and preferablymethyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy stands by way of example and preferably for methoxy, ethoxy,n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkanediyl stands for a straight-chain or branched saturated alkanediylradical having 1 to 6 carbon atoms. A straight-chain or branchedalkanediyl having 1 to 4 carbon atoms is preferred. Preferred exampleswhich may be mentioned are methylene, ethane-1,2-diyl, ethane-1,1-diyl,propane-1,3-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl,butane-1,3-diyl, butane-2,4-diyl, pentane-1,5-diyl, pentane-2,4-diyl,2-methyl-pentane-2,4-diyl.

Alkenyl stands for a straight-chain or branched alkenyl radical having 2to 6 carbon atoms. A straight-chain or branched alkenyl radical having 2to 4 carbon atoms is preferred. Preferred examples which may bementioned are: vinyl, allyl, n-prop-1-en-1-yl, n-but-2-en-1-yl and2-methyl-2-buten-1-yl.

Alkenediyl stands for a straight-chain or branched alkenediyl radicalhaving 2 to 6 carbon atoms. Preference is given to a straight-chain orbranched alkenediyl radical having 3 to 6, particularly preferablyhaving 4 or 5 carbon atoms. Preferred examples which may be mentionedare: propene-1,3-diyl, 2-butene-1,4-diyl and 1-pentene-1,5-diyl.

Alkynediyl stands for a straight-chain or branched alkynediyl radicalhaving 2 to 6 carbon atoms. Preference is given: to a straight-chain orbranched alkynediyl radical having 2 to 4, particularly preferablyhaving 3 or 4, carbon atoms. Preferred examples to be mentioned are:propyne-1,3-diyl and 2-butyne-1,4-diyl.

Cycloalkyl per se and “cycloalk” in cycloalkoxy and cycloalkanediylstands for a cycloalkyl group having usually 3 to 8, preferably 5 to 7,carbon atoms, by way of example and preferably cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

Cycloalkoxy stands by way of example and preferably for cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.

Cycloalkanediyl stands by way of example and preferably forcyclopropane-1,2-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl,cyclopentane-1,2-diyl, cyclopentane-1,3-diyl, cyclohexane-1,2-diyl,cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,2-diyl,cycloheptane-1,3-diyl and cycloheptane-1,4-diyl.

Cycloalkenyl per se and “cycloalken” in cycloalkenediyl and incycloalkenyloxy stands for a cycloalkenyl group having usually 5 to 7carbon atoms, by way of example and preferably cyclopent-2-en-1-yl,cyclopent-3-en-1-yl, cyclohex-2-en-1-yl, cyclohex-3-en-1-yl,cyclohept-2-en-1-yl, cyclohept-3-en-1-yl and cyclohept-4-en-1-yl.

Cycloalkenediyl stands by way of example and preferably forcyclopent-4-ene-1,3-diyl, cyclohex-2-ene-1,4-diyl,cyclohex-4-ene-1,3-diyl and cyclohept-5-ene-1,3-diyl.

Cycloalkenyloxy stands by way of example and preferably forcyclopent-2-en-1-yloxy, cyclopent-3-en-1-yloxy, cyclohex-2-en-1-yloxy,cyclohex-3-en-1-yloxy, cyclohept-2-en-1-yloxy, cyclohept-3-en-1-yloxyand cyclohept-4-en-1-yloxy.

Aryl stands for a mono- to tricyclic aromatic, carbocyclic radicalhaving usually 6 to 10 carbon atoms; by way of example and preferablyphenyl and naphthyl.

Heteroaryl stands for an aromatic, mono- or bicyclic, optionallybenzo-fused, radical having usually 5 to 10, preferably 5 to 6, ringatoms and up to 5, preferably up to 4, heteroatoms from the series S, Oand N, by way of example and preferably thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl,indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl,isoquinolinyl, benzimidazolyl and benzoxazolyl.

Heterocyclyl stands for a mono- or polycyclic, preferably mono- orbicyclic, optionally benzo-fused, nonaromatic heterocyclic radicalhaving usually 5 to 10, preferably 5 to 8, in particular 5 or 6, ringatoms and up to 3, preferably up to 2, heteroatoms and/or hetero groupsfrom the series N, O, S, SO, SO₂. The heterocyclyl radicals may besaturated or partially unsaturated. 5- or 6-membered, monocyclicsaturated heterocylyl radicals, having up to two heteroatoms from theseries O, N and S, which may optionally be benzo-fused, are preferred,such as by way of example and preferably tetrahydrofuran-2-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl,perhydroazepinyl, 1,3-benzodioxolyl, tetrahydro-2H-pyranyl,1,3-dioxanyl, 1,4-dioxanyl, 2,3-dihydro-1,4-dioxinyl,2,3-dihydro-1,4-benzodioxinyl and 4H-1,3-benzodioxinyl.

Halogen stands for fluorine, chlorine, bromine and iodine.

If radicals in the compounds of the invention are substituted, theradicals may, unless specified otherwise, have one or more identical ordifferent substituents. Substitution by up to three identical ordifferent substituents is preferred. Substitution by one substituent isvery particularly preferred.

Preference is given to compounds of the formula (I)

in which

-   A is a 4- to 6-membered nitrogen-containing saturated heterocycle    which is bonded via the nitrogen atom to the keto group, or-   a radical

-    in which    -   E is (C₅-C₆)-cycloalkanediyl,    -   o is 0 or 1,    -   R³ is hydrogen, and    -   * is the point of linkage to the keto group,-   m is 0 or 1,-   n is 1, 2 or 3,-   R¹ is hydrogen,-   R² is hydrogen,-   X is a bond or O,-   Y is O or *—NH—C(═O)—,    -   in which    -   * is the point of linkage to the phenyl ring, and-   Z is located in the position meta or para to the substituent X and    is either (C₇-C₉)-alkoxy, which may comprise 1 further oxygen atom    in the chain, or-   a radical

-    in which    -   G is a bond or O.    -   L is (C₁-C₆)-alkanediyl or (C₃-C₆)-alkenediyl,    -   M is a bond, O or S,    -   R⁴ is phenyl, naphthyl, biphenylyl, phenoxyphenyl,        benzyloxyphenyl, (E)-phenylvinylphenyl, 2-phenylethylphenyl,        tetrahydronaphthyl, benzyl, 1,3-dioxanyl, 1,4-dioxanyl,        dimethyl-1,3-dioxanyl, tetrahydro-2H-pyranyl, (C₃-C₇)-cycloalkyl        or (C₃-C₇)-cycloalkylmethyl, where phenyl, naphthyl, biphenylyl,        phenoxyphenyl, benzyloxyphenyl, (E)-phenylvinylphenyl,        2-phenylethylphenyl, tetrahydronaphthyl, benzyl, cycloalkyl and        cycloalkylmethyl in turn may be substituted up to three times        independently of one another by halogen, cyano, nitro,        tri-fluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl,        (C₁-C₆)-alkoxy, (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkylmethoxy or        (C₃-C₇)-cycloalkoxy, and    -   * is the point of linkage to the phenyl ring,        and the salts, hydrates, hydrates of the salts and solvates        thereof.

Particular preference is given compounds of the formula (I) in which

-   n is 3.

Particular preference is likewise given to compounds of the formula (I)in which

-   X is a bond.

Particular preference is likewise given to compounds of the formula (I)in which

-   Y is O.

Particular preference is likewise given to compounds of the formula (I)in which

-   Z is located in the position para to the substituent X.

Particular preference is likewise given to compounds of the formula (I)

in which

-   A-[CH₂]_(m)—CO₂R¹ is a radical

-    in which    -   * is the point of linkage to the keto group,-   n is 3,-   R² is hydrogen,-   X is a bond,-   Y is O, and-   Z is located in the position para to the substituent X and is either    n-octyloxy, n-heptyloxy, or-   a radical

-    in which    -   * is the point of linkage to the phenyl ring, or-   a radical

-    in which    -   G is O,    -   L is methanediyl, n-propanediyl or n-butanediyl,    -   M is a bond or O,    -   R⁴ is phenyl, 4-biphenylyl, 4-phenoxyphenyl, 4-benzyloxyphenyl,        1,2,3,4-tetrahydronaphth-6-yl, 5,5-dimethyl-1,3-dioxan-2-yl or        cyclohexyl, where phenyl in turn may be substituted once by        halogen, trifluoromethoxy, (C₃-C₄)-alkyl, (C₃-C₄)-alkoxy,        cyclopentyl, cyclo-hexyl or (C₃-C₆)-cycloalkylmethoxy, and    -   * is the point of linkage to the phenyl ring,        and the salts, hydrates, hydrates of the salts and solvates        thereof.

Very particular preference is given to compounds of the formula (I)

in which

-   A-[CH₂]_(m)—CO₂R¹ is a radical

-    in which    -   * is the point of linkage to the keto group,-   n is 3,-   R² is hydrogen,-   X is a bond,-   Y is O, and-   Z is located in the position para to the substituent X, and is    either    -   n-octyloxy, n-heptyloxy, or-   a radical

-    in which    -   * is the point of linkage to the phenyl ring, or-   a radical *—O—CH₂—R⁴,-    in which    -   R⁴ is phenyl, 4-biphenylyl, 4-phenoxyphenyl, 4-benzyloxyphenyl        or 1,2,3,4-tetrahydronaphth-6-yl, where phenyl in turn may be        substituted once by trifluoromethoxy, n-propyl, n-butyl,        tert-butyl, n-propyloxy, isopropyloxy, isobutyloxy, cyclohexyl        or cyclopropylmethoxy, and    -   * is the point of linkage to the phenyl ring, or-   a radical *—CH₂—CH₂—CH₂—R⁴,-    in which    -   R⁴ is 4-chlorophenyl, 5,5-dimethyl-1,3-dioxan-2-yl or        cyclohexyl, and    -   * is the point of linkage to the phenyl ring, or-   a radical *—O—CH₂—CH₂—CH₂—CH₂—O—R⁴,-    in which    -   R⁴ is phenyl or cyclohexyl, and    -   * is the point of linkage to the phenyl ring,        and the salts, hydrates, hydrates of the salts and solvates        thereof.

Especial preference is given to compounds of the formula (I)

in which

-   A-[CH₂]_(m)—CO₂R¹ is a radical

-    in which    -   * is the point of linkage to the keto group,-   n is 3,-   R² is hydrogen,-   X is a bond,-   Y is O, and-   Z is located in the position para to the substituent X and is a    radical

-    in which    -   * is the point of linkage to the phenyl ring,        and the salts, hydrates, hydrates of the salts and solvates        thereof.

Very particular preference is given in particular to the followingcompounds of formula (I):

-   3-{[(3-carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoic    acid,-   3-{[(3-carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(3-cyclohexylpropoxy)phenyl]-propoxy}benzoic    acid,-   3-{[(3-carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[4-(cyclohexyloxy)butoxy]-phenyl}propoxy)benzoic    acid,-   1-(5-carboxy-2-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}benzoyl)piperidine-4-carboxylic    acid,-   3-{[(3-carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-isopropoxybenzyl)oxy]-phenyl}propoxy)benzoic    acid,-   3-{[3-(carboxymethyl)azetidin-1-yl]carbonyl}-4-{3-[4-(3-cyclohexylpropoxy)-phenyl]propoxy}benzoic    acid,-   3-{[(3-carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(1E)-5-phenoxypent-1-en-1-yl]-phenyl}propoxy)benzoic    acid.

Preference is likewise given to compounds of the formula (I) in which

-   A is a 4- to 7-membered nitrogen-containing saturated heterocycle    which is bonded via the nitrogen atom to the keto group, which may    comprise a further nitrogen atom in the ring and which optionally    has a carbonyl group adjacent to a nitrogen atom, or-   a radical

-    in which    -   E is (C₃-C₇)-cycloalkanediyl, (C₅-C₇)-cycloalkenediyl or is 5-        to 10-membered heterocyclyl which is bonded via a carbon atom to        the [CH₂]_(o) group,    -   o is 0, 1 or 2,    -   R³ is hydrogen or (C₁-C₆)-alkyl, and    -   * is the point of linkage to the keto group,-   m is 0, 1 or 2,-   n is 1, 2, 3 or 4,-   R¹ is hydrogen or (C₁-C₆)-alkyl,-   R² is hydrogen or (C₁-C₆)-alkyl,-   X is a bond, O, NH, N-methyl or N-acetyl,-   Y is O, *—NH—C(═O)— or NH,    -   in which    -   * is the point of linkage to the phenyl ring, and-   Z a radical

-    which is located in the position meta or para to the substituent X,    -   in which    -   G is a bond, O or S,    -   L is (C₁-C₆)-alkanediyl, (C₃-C₆)-alkenediyl or        (C₃-C₆)-alkynediyl,    -   M is a bond, O or S,    -   R⁴ is (C₆-C₁₀)-aryl, biphenylyl, heteroaryl, 5- to 10-membered        hetero-cyclyl or (C₃-C₇)-cycloalkyl, where aryl, biphenylyl,        heteroaryl, heterocyclyl and cycloalkyl in turn may be        substituted up to three times independently of one another by        halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy,        (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₂-C₆)-alkenyl,        (C₃-C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl, (C₃-C₇)-cycloalkoxy or        (C₅-C₇)-cycloalkenyloxy,    -   * is the point of linkage to the phenyl ring,        and the salts, hydrates, hydrates of the salts and solvates        thereof.

Preference is likewise given to compounds of the formula (I),

in which

-   A a radical

-    in which    -   * is the point of linkage to the keto group, and    -   ^ is the point of linkage to the

-   -    group,

-   m is 0 or 1,

-   n is 2 or 3,

-   R¹ is hydrogen,

-   R² is hydrogen,

-   X is a bond,

-   Y is O or *—NH—C(═O)—,    -   in which    -   * is the point of linkage to the phenyl ring, and

-   Z is a radical

-    which is located in the position meta or para to the substituent X,    -   in which    -   R⁴ and R⁴ are, independently of one another, fluorine, chlorine,        bromine, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl or        (C₁-C₆)-alkoxy, and    -   * is the point of linkage to the phenyl ring,        and the salts, hydrates, hydrates of the salts and solvates        thereof.

Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

The present invention also relates to a process for preparing thecompounds of the formula (I), which is characterized in that either

-   [A] compounds of the formula (II)

-    in which    -   R² is (C₁-C6)-alkyl and    -   n, X, Y and Z have the meaning indicated above,        are reacted with compounds of the formula (III)

-   -   in which    -   R¹ is (C₁-C₆)-alkyl, and    -   m and A have the meaning indicated above, or

-   [B1] compounds of the formula (IVa)

-    in which    -   Q¹ is a suitable leaving group such as, for example, halogen,        mesylate or tosylate, and    -   n, X and Z have the meaning indicated-above,        are reacted with compounds of the formula (Va)

-   -   in which    -   R¹ and R² are (C₁-C₆)-alkyl, and    -   A and m have the meaning indicated above, or

-   [B2] compounds of the formula (IVb)

-    in which    -   Q² is an acid chloride group, and    -   n, X and Z have the meaning indicated above,        are reacted with compounds of the formula (Vb)

-   -   in which    -   R¹ and R² are (C₁-C₆)-alkyl, and    -   A and m have the meaning indicated above, or

-   [B3] compounds of the formula (IVa)

-    in which    -   Q¹ is a suitable leaving group such as, for example, halogen,        mesylate or tosylate, and    -   n, X and Z have the meaning indicated above,        are reacted with compounds of the formula (Vb)

-   -   in which    -   R¹ and R² are (C₁-C₆)-alkyl and    -   A and m have the meaning indicated above, or

-   [C] compounds of the formula (XII)

-    in which    -   R¹ and R² are (C₁-C₆)-alkyl, and    -   n, m, X, Y and A have the meaning indicated above,        are reacted with compounds of the formula (XIII)        R⁴-M-L-Q³  (XIII),    -   in which    -   Q³ is a suitable leaving group such as, for example, halogen,        preferably bromine, chlorine or iodine, or mesylate or tosylate,        and    -   R⁴, M and L have the meaning indicated above, or-   [D] the two ester groups in compounds prepared by process step [A],    [B 1], [B2], [B3] or [C] are hydrolysed.

The process of the invention can be illustrated by way of example by thefollowing formula scheme:

Compounds of the formula (II) can be prepared for example by reactingcompounds of the formula (IVa) with compounds of the formula (VI)

in which

-   R² is (C₁-C₆)-alkyl,    to give compounds of the formula (VII)

in which

-   R² is (C₁-C₆)-alkyl,-   Y is O, and-   n, X and Z have the meaning indicated above,    and subsequently oxidizing the aldehyde group.

Compounds of the formula (IVa) can be prepared for example by convertingcompounds of the formula (VIII)

in which

-   R⁵ is hydrogen or an alkyl radical, and-   n, X and Z have the meaning indicated above,    by reduction of the carboxylic acid or ester group into the    corresponding alcohols of the formula (IX)

in which

-   n, X and Z have the meaning indicated above,    and finally converting the hydroxyl group into a leaving group such    as, for example, halogen, mesylate or tosylate.

Compounds of the formula (IVb) can be prepared for example fromcompounds of the formula (VIII) by, in the case where R⁵ in compounds ofthe formula (VIII) is hydrogen, converting the carboxylic acid groupinto the corresponding acid chloride or, in the case of compounds of theformula (VIII) in which R⁵ is an alkyl group, in a preceding stephydrolysing the corresponding ester group initially to the carboxylicacid group.

Compounds of the formula (Va) can be prepared for example by reactingcompounds of the formula (III) with compounds of the formula (X)

in which,

-   Q⁴ is hydroxyl or chlorine, and-   R¹ is (C₁-C₆)-alkyl.

Compounds of the formula (Vb) can be prepared for example by, in a firstamide coupling reaction, reacting compounds of the formula (III) withcompounds of the formula (XI)

in which

-   Q⁴ is hydroxyl or chlorine, and-   R² is (C₁-C₆)-alkyl,    and finally reducing the nitro group to the corresponding amino    group.

Compounds of the formula (VIIIa), corresponding to compounds of theformula (VIII), in which X is an oxygen atom and R⁵ is an alkyl radical,can be prepared for example by reacting compounds of the formula (XIV)

in which

-   Z has the meaning indicated above,    with compounds of the formula (XV)

in which

-   Q⁵ is a suitable leaving group such as, for example, halogen,    mesylate or tosylate, and-   R⁵ is an alkyl radical.

Compounds of the formula (VIIIb), corresponding to compounds of theformula (VIII), in which X is a bond or —CH═CH—, Z is *—O-L-M-R⁴ and R⁵is an alkyl radical, can be prepared for example by reacting compoundsof the formula (XIII) with compounds of the formula (XVI)

in which

-   R⁵ is an alkyl radical,-   X is a bond or —CH═CH—, and-   n has the meaning indicated above.

Compounds of the formula (VIIIc), corresponding to compounds of theformula (VIII), in which X is a bond, Z is *-L-M-R⁴ and R⁵ is an alkylradical, can be prepared for example by reacting compounds of theformula (XVII)—R⁴-M-L-PPh₃ ⁺Br⁻  (XVII),in which

-   R⁴, M and L have the meaning indicated above,    with compounds of the formula (XVIII)

in which

-   R⁵ is an alkyl radical, and-   n has the meaning indicated above.

Compounds of the formula (IXa), corresponding to compounds of theformula (IX), in which X is —C≡C— and n is 1, can be prepared forexample by reacting compounds of the formula (XIX)

in which

-   Q⁶ is a suitable leaving leaving group such as, for example,    bromine, iodine or trifluoromethanesulphonate, and-   Z has the meaning indicated above,    with propargyl alcohol.

Compounds of the formula (XII) can be prepared for example by reactingcompounds of the formula (Va) with compounds of the formula (XX)

in which

-   Q¹ is a suitable leaving group such as, for example, halogen,    mesylate or tosylate,-   PG is a suitable protective group such as, for example, a silyl    protective group, and-   n and X have the meaning indicated above,    and subsequently eliminating the protective group by conventional    methods known to the skilled person.

Compounds of the formula (XX) can be prepared for example by reactingcompounds of the formula (XVI) with conventional protective groupreagents known to the skilled person, such as, for example,triisopropylsilyl chloride, and subsequently converting the carboxylicacid or ester group into the leaving group Q¹ as described for compoundsof the formula (IVa).

Compounds of the formula (I) in which R¹ is hydrogen can also beprepared from the corresponding benzyl esters (R¹=benzyl) instead offrom the corresponding alkyl esters of the compounds of the formulae(III), (Va) or (Vb) R¹=alkyl).

In the amide couplings of process steps (II)+(III)->(I); (III)+(X)->(Va)(for Q⁴=hydroxyl) and of the first constituent step (III)+(XI)->(Vb)(for Q⁴=hydroxyl), the amines are preferably employed in the form oftheir hydrochlorides. The reactions preferably take place under standardconditions in the presence of generally customary reagents for amide orpeptide coupling such as, for example,N-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDC) and1-hydroxy-1H-benzotriazole hydrate (HOBT) in the presence of auxiliarybases such as triethylamine or diisopropylethylamine, in solvents suchas dichloromethane or dimethylformamide at room temperature.

In the amide couplings of process steps (III)+(X)->(Va) (forQ⁴=chlorine) and of the first constituent step (III)+(XI)->(Vb) (for Q⁴equal to chlorine), the amines are preferably employed in the form oftheir hydrochlorides. The reactions preferably take place under standardconditions in the presence of auxiliary bases such as triethylamine ordiisopropylethylamine, in solvents such as diethyl ether,tetrahydro-furan or methylene chloride at temperatures between 0° C. androom temperature.

The ester hydrolysis in the preparation of compounds (I) by process [D],in which R¹ and R² are hydrogen, and in the first constituent step ofthe reaction (VIII)->(IVb) preferably takes place in the presence ofaqueous alkali metal hydroxide solution such as, for example, 2-molarsodium hydroxide solution, at temperatures between room temperature and70° C. with addition of water-miscible organic solvents such as, forexample, methanol or tetrahydrofuran or mixtures thereof.

Process steps (IVa)+(Va)->(I); (IVa)+(Vb)->(I); (IVa)+(VI)->(VII);(XII)+(XIII)->(I); (XIV)+(XV)->(VIIIa); (XIII)+(XVI)->(VIIIb) and(Va)+(XX)->(XII) preferably take place in inert solvents such as, forexample, tetrahydrofuran, dioxane, dimethylformamide,N-methylpyrrolidone, acetonitrile, acetone or butyronitrile, in thepresence of auxiliary bases such as, for example, potassium carbonate,sodium carbonate, caesium carbonate, triethylamine,ethyldiisopropyl-amine or pyridine in a temperature range between roomtemperature and the boiling point of the particular solvent.

An alternative possibility for the preparation of compound (VII) is alsoby reacting the alcohol (IX) with compound (VI) under Mitsunobu reactionconditions. Solvents suitable for this purpose are, in particular,ethers such as, for example, tetrahydrofuran or chlorohydrocarbons suchas, for example, dichloromethane. The reaction takes place in thepresence of triphenylphosphine and azo compounds such as, for example,diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).The preferred temperature range for carrying out the reaction is between−10° C. and room temperature.

Process step (IVb)+(Vb)->(I) preferably takes place in an inert solventsuch as, for example, in ether, tetrahydrofuran, dichloromethane orchloroform in the presence of an auxiliary base such as, for example,triethylamine, diisopropylethylamine or pyridine at temperatures between0° C. and room temperature.

Process step (VII)->(II) takes place under conventional conditions knownto the skilled person for oxidizing aldehyde groups to carboxylic acidgroups. Oxidation with sodium chlorite in the presence of hydrogenperoxide and sodium dihydrogen phosphate or in the presence of sulphamicacid in a solvent mixture composed of water with acetonitrile ortetrahydrofuran or dioxane in the temperature range between 0° C. androom temperature is very suitable for example in this connection.

Process step (VIII)->(IX) takes place under conventional conditionsknown to the skilled person for reducing carboxylic acid or ester groupsto the corresponding alcohol groups such as, for example, with complexmetal hydrides such as lithium aluminium hydride in inert solvents suchas, for example, tetrahydrofuran in the temperature range between 0° C.and the boiling point of the particular solvent.

Conversion of the alcohol function into a leaving group Q¹ in processstep (IX)->(IVa) can take place in various ways known to the skilledperson. The reaction to give the corresponding bromide preferably takesplace in tetrahydrofuran as solvent at room temperature with a mixtureof triphenylphosphine and tetrabromomethane or in dichloromethane assolvent in the temperature range between 0° C. and room temperature withphosphorus tribromide, where appropriate in the presence of pyridine.The reaction to give the corresponding mesylate or tosylate preferablytakes place in dichloromethane as solvent in the temperature rangebetween 0° C. and room temperature with methanesulphonyl chloride orpara-toluenesulphonyl chloride in the presence of tertiary amines suchas, for example, triethylamine or diisopropylethylamine.

The carboxylic acid group obtained in the first constituent step of thereaction (VIII)->(IVb) is converted by chlorination into thecorresponding acid chloride. Preferred chlorination reagents are thionylchloride or oxalyl chloride. The reaction takes place where appropriatein the presence of catalytic amounts of dimethylformamide, it beingpossible to add halogenated hydrocarbons such as, for example,dichloromethane or chloroform as solvents. The reaction temperature inthis case is between 0° C. and the boiling point of the particularsolvent or chlorination reagent.

Reduction of the nitro group in the second constituent step of thereaction (III)+(XI)->(Vb) can take place for example with tin(II)chloride. Reduction with hydrogen on noble metal catalysts such as, forexample, palladium on charcoal as support material, under a hydrogenpressure of from one to four bar and at room temperature in methanol,ethanol or ethyl acetate as solvent is preferred.

Process step (XVII)+(XVII)->(VIIIc) takes place under conventionalconditions known to the skilled person for the Wittig reaction. Thereaction preferably takes place in an inert solvent such as, forexample, in hexane, diethyl ether, toluene or tetrahydrofuran,particularly preferably in tetrahydrofuran, in the presence of a strongbase such as, for example n-butyllithium or sodiumbis(trimethylsilyl)amide at temperatures between −50° C. and roomtemperature.

Process step (XIX)->(IXa) preferably takes place in triethylamine assolvent in the presence of copper(I) iodide, a palladium(II) salt suchas, for example, dichlorobis(triphenylphosphine)palladium([Pd(PPh₃)₂]Cl₂) and triphenylphosphine at temperatures between 50° C.and 70° C.

The compounds of the formula (III), (VI), (VIII), (X), (XI), (XIII),(XIV), (XV), (XVI), (XVII), (XVIII), (XIX) and (XX) are known per se tothe skilled person or can be prepared by conventional processes knownfrom the literature.

It is additionally possible to prepare compounds of the formula (I)

in which

-   A is

-   R¹ is hydrogen,-   R² is hydrogen,-   n is 3,-   X is a bond,-   Y is O,-   Z is located in the position para to the substituent X,-   G is O, and-   E, L, M, R⁴, m and o have the meaning indicated above    also with the aid of solid-phase synthesis:    onto a solid phase from the group of micro- or macroporous    polystyrene (PS) crosslinked with between 1 and 30% divinylbenzene    (DVB), poly-styrene/polyethylene glycol (PS/PEG) graft or block    copolymers and functionalized glass surfaces (controlled pore glass,    CPG), primary amines are attached as imine via a benzaldehyde    functionality present on the solid phase and are then reduced to the    secondary amine. For this purpose preferably    4-(4-formyl-3-methoxyphenoxy)butyrylaminomethyl resin based on PS    crosslinked with 2% DVB (“Pol-CHO”, Nova Biochem) is reacted with a    two- to five-fold excess of a cyclic or acyclic β-, γ- or δ-amino    acid which is t-butyl- or t-hexyl-protected on the acid    functionality, preferably as hydrochlorides thereof, in    dimethylformamide, N-methylpyrrolidone, dichloromethane, dioxane,    tetrahydrofuran, toluene or other suitable solvents with or without    dehydrating agents such as trimethyl orthoformate, sodium sulphate    or magnesium sulphate, where appropriate in the presence of    auxiliary bases such as potassium carbonate, sodium carbonate,    triethylamine, ethyldiisopropylamine and pyridine at temperatures    between room temperature and 50° C. for 2 to 24 hours (reaction a):

The solid phase is then either washed one or more times with varioussolvents such as dimethylformamide, N-methylpyrrolidone,dichloromethane, dioxane, tetrahydrofuran, toluene, acetonitrile ormethanol or directly reacted further in the subsequent reduction. Forthis purpose, the solid phase is reacted with a two- to ten-fold excessof reducing agents such as sodium borohydride, sodium cyanoborohydride,sodium triacetoxyborohydride or tetrabutylammonium borohydride insolvents such as dichloromethane, dimethylformamide, tetrahydrofuran ormethanol or else mixtures of these at temperatures between −78° C. androom temperture, where appropriate with addition of up to 100equivalents of acetic acid for 0.5 to 18 hours (reaction b).

After the solid phase has been washed and dried by conventionalprocesses known to the skilled person, it is then reacted with2-hydroxy-5-methoxycarbonylbenzoic acid.

The reagents known to the skilled person for amide or peptide couplingare employed for this purpose. Examples thereof areN-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDC) and1-hydroxy-1H-benzotriazole hydrate (HOBT), which are employed in thepresence of auxiliary bases such as triethylamine ordiisopropylethylamine in solvents such as dichloromethane ordimethylformamide at room temperature (reaction c).

After the solid phase has been washed and dried by conventionalprocesses known to the skilled person, it is then reacted with 1 to 5equivalents of 3-bromo-1-(4-tert-butyldimethylsilyloxyphenyl)propane or3-bromo-1-(4-tri-iso-propylsilyloxy-phenyl)propane and a base from thegroup of sodium carbonate, sodium hydride, potassium carbonate andcaesium carbonate in polar aprotic solvents such as tetra-hydrofuran,dioxane, dimethylformamide, N-methylpyrrolidone, where appropriate withaddition of 18-crown-6 or tetrabutylammonium iodide at temperaturesbetween room temperature and the boiling point of the appropriatesolvent for 1-24 hours (reaction d). After the solid phase has beenwashed and dried by conventional processes known to the skilled personit is then reacted with 2 to 10 equivalents of tetrabutylammoniumfluoride in tetrahydrofuran at room temperature for 2-24 hours, and thesilyl protective group is thus eliminated (reaction e).

After the solid phase has been washed and dried by conventionalprocesses known to the skilled person, it is then reacted with compoundsof the formula R⁴-M-L-Q³ where Q³ is chlorine, bromine, iodine,mesylate, tosylate or another leaving group known to the skilled personin nucleophilic substitution reactions. The reactions are carried outusing a base from the group of sodium carbonate, sodium hydride,potassium carbonate and caesium carbonate in polar aprotic solvents suchas tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone,where appropriate with addition of 18-crown-6 or tetrabutylammoniumiodide, at temperatures between room temperature and the boiling pointof the particular solvent for 1-24 hours (reaction f). After the solidphase has been washed and dried by conventional processes known to theskilled person, the methyl ester on it is then hydrolyzed with basessuch as sodium carbonate, potassium carbonate, caesium carbonate, sodiumhydroxide or potassium hydroxide in mixtures of polar solvents such astetrahydrofuran, dioxane or N-methylpyrrolidone with water or methanolat temperatures between 0° C. and 60° C. (reaction g).

The solid phase is thoroughly washed with conventional solvents such asmethanol, dichloromethane, water, dimethylformamide,N-methylpyrrolidone, dioxane, tetrahydrofuran, acetonitrile or tolueneand then dried. The product is subsequently eliminated from the solidphase with a mixture of 20-70% trifluoroacetic acid in dichloromethane,with spontaneous removal of the t-butyl protective group (reaction h).After filtration to remove the solid phase and concentration in vacuo attemperatures between 0° C. and 100° C., the products have puritiesbetween 75% and 100%.

The compounds of the invention show a valuable pharmacological andpharmacokinetic spectrum of effects which could not have been predicted.They are therefore suitable for use as medicaments for the treatmentand/or prophylaxis of diseases in humans and animals.

The pharmaceutical activity of the compounds of the invnetion of theformula (I) can be explained by their effect as selective antagonists ofthe cysteinyl-leukotriene receptor 2.

Cysteinyl-leukotriene receptor antagonists referred to as “selective”for the purposes of the present invention are those which inhibit theactivity of the cysteinyl-leukotriene receptor 2 at a concentrationwhich is lower by a factor of more than 10, preferably by a factor ormore than 100, in particular by a factor of more than 1000, than anequivalent activity of the cysteinyl-leukotriene receptor 1. Concerningthe test methods for determining the selectivity, reference may be madeto the test methods described in section B 1. and B 2.

Modulators of the cysteinyl-leukotriene receptors referred to as“antagonists” for the purposes of the present invention are those havingantagonistic activity and comprising merely a partial, preferably nomeasurable, agonistic component.

The compounds of the formula (I) are suitable for the prophylaxis and/ortreatment of various disorders, in particular of cardiovasculardisorders.

Preferred examples which may be mentioned are: atrial and ventriculararrhythmias, myocardial infarction, arteriosclerosis, heart failure,stable and unstable angina pectoris, myocardial ischaemia, transientischaemic attacks, stroke, inflammatory cardiovascular disorders,coronary heart disease, peripheral and cardiac vascular disorders,peripheral blood flow disturbances, restenoses such as followingthrombolysis therapies, percutaneous transluminal angioplasties (PTA)and transluminal coronary angioplasties (PTCA), pulmonary hypertension,coronary spasms, thromboses, thromboembolic disorders, bypassoperations, heart transplants, oedema formation, shock, high bloodpressure, acute renal failure, inflammatory disorders, asthmaticdisorders, chronic obstructive airways disease (COPD), states of pain,prostate hypertrophy, inflammatory skin disorders, placentalinsufficiency, placentation disturbances, incontinence, cystitis,hyperactive bladder, disorders of the adrenal such as, for example,phaeochromocytoma and Waterhouse-Friderichsen syndrome, intestinaldisorders such as, for example, Crohn's disease or diarrhoea.

The present invention further relates to the use of the compounds of theinvention for the treatment and/or prophylaxis of disorders, inparticular of the aforementioned disorders.

The present invention further relates to the use of the compounds of theinvention for producing a medicament for the treatment and/orprophylaxis of disorders, in particular of the aforementioned disorders.

The present invention further relates to a method for the treatmentand/or prophylaxis of disorders, in particular of the aforementioneddisorders, using an effective amount of the compounds of the invention.

The present invention further relates to medicaments comprising at leastone compound of the invention and one or more other active ingredients,in particular for the treatment and/or prophylaxis of the aforementioneddisorders. Examples of suitable and preferred active ingredients in thecombination which may be mentioned are: cysteinyl-leukotriene receptor 1antagonist, cysteinyl-leukotriene-biosynthesis inhibitor, thrombolytics,a platelet aggregation inhibitor, β-blockers, nitrates, Ca channelblockers and/or an anti-inflammatory active ingredient such as, forexample, a cyclooxygenase inhibitor.

The compounds of the invention may have systemic and/or local effects.They can for this purpose be administered in a suitable way, such as,for example, by the oral, parenteral, pulmonary, nasal, sublingual,lingual, buccal, rectal, dermal, transdermal, conjunctival or otic routeor as implant or stent.

The compounds of the invention can be administered in suitableadministration forms for these administration routes.

Administration forms suitable for oral administration are those whichfunction according to the state of the art and deliver the compounds ofthe invention in a rapid and/or modified way, and which contain thecompounds of the invention in crystalline and/or amorphized and/ordissolved form, such as, for example, tablets (uncoated or coatedtablets, for example with coatings which are resistant to gastric juiceor dissolve slowly or are insoluble and which control the release of thecompound of the invention), tablets which rapidly disintegrate in themouth, or films/wafers, films/lyophilisates, capsules (for example hardor soft gelatin capsules), sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (e.g. intravenous, intraarterial, intracardiac, intraspinal orintralumbar) or with inclusion of an absorption (e.g. intramuscular,subcutaneous, intracutaneous, percutaneous or intraperitoneal).Administration forms suitable for parenteral administration are, interalia, injection and infusion preparations in the form of solutions,suspensions, emulsions, lyophilisates or sterile powders.

Examples suitable for other administration routes are medicinal formsfor inhalation (inter alia powder inhalators, nebulizers), nasal drops,solutions, sprays; tablets for lingual, sublingual or buccaladministration, films/wafers or capsules, suppositories, preparationsfor the ears or eyes, vaginal capsules, aqueous suspensions (lotions,shaking mixtures), lipophilic suspensions, ointments, creams,transdermal therapeutic systems (such as, for example, plasters), milk,pastes, foams, dusting powders, implants or stents.

Parenteral, in particular intravenous administration is preferred, e.g.as iv bolus injection (i.e. as single dose, e.g. by syringe), shortinfustion (i.e. infusion over a period of up to one hour) or longinfusion (i.e. infusion over a period of more than one hour). Theadministered volume may in these cases be, depending on the specificconditions, between 0.5 to 3.0, in particular 1 to 20, ml on iv bolusinjection, between 25 to 500, in particular 50 to 250, ml on shortinfusion and between 50 to 1000, in particular 100 to 500, ml on longinfusion. It may for this purpose be advantageous for the activeingredient to be provided in the solid form (e.g. as lyophilisate or assalt) and to be dissolved in the dissolving medium only directly beforeadministration.

It is necessary in these cases that the administration forms be sterileand pyrogen-free. They may be based on aqueous or mixtures of aqueousand organic solvents. These include, for example, aqueous solutions,mixtures of aqueous and organic solvents (especially ethanol,polyethylene glycol (PEG) 300 or 400), aqueous solutions containingcyclodextrins or aqueous solutions containing emulsifiers(surface-active solubilizers, e.g. lecithin or Pluronic F 68, SolutolHS15, Cremophor). Aqueous solutions are preferred.

Formulations suitable for parenteral administration are those which aresubstantially isotonic and euhydric, e.g. those with a pH between 3 and11, preferably between 6 and 8, in particular around 7.4.

Injection solutions are packaged in suitable containers made of glass orplastic, e.g. in vials. The solution can be removed directly therefromand administered. In the case of a lyophilisate, it is dissolved in thevial by injecting a suitable solvent and is then removed. Infusionsolutions are packaged in suitable containers made of glass or plastic,e.g. in bottles or collapsible plastic bags.

The compounds of the invention can be converted into the statedadministration forms. This can take place in a manner known per se bymixing with inert, non-toxic, pharmaceutically suitable excipients.These excipients include, inter alia, carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersants or wetting agents(for example sodium dodecylsulphate, polyoxysorbitan oleate), binders(for example polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants such as, for example,ascorbic acid), colours (e.g. inorganic pigments such as, for example,iron oxides) and masking tastes and/or odours.

The present invention further relates to medicaments which comprise atleast one compound of the invention, normally together with one or moreinert, non-toxic, pharmaceutically suitable excipients, and to the usethereof for the aforementioned purposes.

It has generally proved advantageous both in human and in veterinarymedicine to administer the active ingredient of the invention in totalamounts of about 0.01 to about 700, preferably 0.01 to 100 mg/kg of bodyweight every 24 hours, where appropriate in the form of a plurality ofsingle doses, to achieve the desired results. A single dose preferablycontains the active ingredient of the invention in amounts of about 0.1to about 80, in particular 0.1 to 30, mg/kg of body weight.

It may nevertheless be necessary to deviate from the stated-amounts, inparticular as a function of body weight, administration route,individual behaviour towards the active ingredient, type of preparationand time or interval over which administration takes place. Thus, it mayin some cases be sufficient to make do with less than the aforementionedminimum amount, whereas in other cases the stated upper limit must beexceeded. Where larger amounts are administered, it may be advisable todivide them into a plurality of single doses over the day.

The percentage data in the following tests and examples are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data for liquid/liquidsolutions are in each case based on volume.

A. EXAMPLES

Abbreviations:

b.p. boiling point conc. concentrated DCI direct chemical ionization (inMS) TLCM dichloromethane DIEA N,N-diisopropylethylamine DMSO dimethylsulphoxide DMF N,N-dimethylformamide EA ethyl acetate (acetic acid ethylester) EI electron impact ionization (in MS) ESI electrospray ionization(in MS) h Hour HPLC high pressure, high performance liquidchromatography LC-MS coupled liquid chromatography/mass spectroscopy LDAlithium diisopropylamide m.p. melting point MPLC medium pressure, mediumperformance liquid chromatography MS mass spectroscopy NMR nuclearmagnetic resonance spectroscopy RP-HPLC reverse phase HPLC RT roomtemperature R_(f) retention index (in TLC) R_(t) retention time (inHPLC) sat. Saturated TFA trifluoroacetic acid THF Tetrahydrofuran TLCthin-layer chromatographyHPLC and LC-MS methods:Method 1 (HPLC)

Instrument: HP 1100 with DAD; column: Kromasil RP-18, 60 mm×2 mm, 3.5μm; eluent A: 5 ml HClO₄/l of water, eluent B: acetonitrile; gradient: 0min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; flow rate: 0.75ml/min; oven: 30° C.; UV detection: 210 nm.

Method 2 (HPLC)

Instrument: HP 1100 with DAD; column: Kromasil RP-18, 60 mm×2 mm, 3.5μm; eluent A: 5 ml HClO₄/l of water, eluent B: acetonitrile; gradient: 0min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; flow rate: 0.75ml/min; oven: 30° C.; UV detection: 210 nm.

Method 3 (LC-MS)

MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance2790; column: Grom-Sil 120 ODS-4 HE 50 mm×2 mm, 3.0 μm; eluent B:acetonitrile+0.05% formic acid, eluent A: water+0.05% formic acid;gradient: 0.0 min 5% B→2.0 min 40% B→4.5 min 90% B→5.5 min 90% B; oven:45° C.; flow rate: 0.0 min 0.75 ml/min→4.5 min 0.75 ml/min→5.5 min 1.25ml/min; UV detection: 210 nm.

Method 4 (HPLC)

Instrument: HP 1100 with DAD; column: Kromasil RP-18, 60 mm×2 mm, 3.5μm; eluent A: 5 ml of HClO₄/l of water, eluent B: acetonitrile;gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 15 min 90% B; flowrate: 0.75 ml/min; oven: 30° C.; UV detection: 210 nm.

Method 5 (HPLC)

Instrument: Symmetry TM C18 3.9*150 mm; flow 1,5 ml/min; eluent water(A)/acetonitrile (B); gradient −0.6 min 10% of B, −3.8 min 100% B, −5.0min 100% B, −5.5 min 10% B; stop time 6.0 min; injection volume 10 μl ;diode array detector signal 214 nM and 254 nm.

Method 6 (LC-MS)

MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance2795; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm; eluentA: 1 l of water+0.5 ml of 50% strength formic acid, eluent B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90%A→2.5 min 30% A→3.0 min 5%/A→4.5 min 5%/A; flow rate: 0.0 min 1 ml/min,2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 7 (LC-MS)

MS apparatus type: Micromass ZQ; HPLC apparatus type: HP 1100 series; UVDAD; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm; eluentA: 1 l of water+0.5 ml of 50% strength formic acid, eluent B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1 ml/min,2.5 min/3.0 min/4.5 min. 2 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 8 (LC-MS)

MS apparatus type: Micromass ZQ; HPLC apparatus type: BP 11100 series;UV DAD; column: Grom-Sil 120 ODS-4 HE 50 mm×2 mm, 3.0 μm; eluent A:water+500 μl of 50% strength formic acid/1, eluent B: acetonitrile+500μl of 50% strength formic acid/1; gradient: 0.0 min 0% B→2.9 min 70%B→3.1 min 90%/B→4.5 min 90% B; oven: 50° C.; flow rate: 0.8 ml/min; UVdetection: 210 nm.

Method 9 (LC-MS)

MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance2795; column: Merck Chromolith SpeedROD RP-18e 50 mm×4.6 mm; eluent A:water+500 μl of 50% strength formic acid/1; eluent B: acetonitrile+500μl of 50% strength formic acid/1; gradient: 0.0 min 10% B→3.0 min 95%B→4.0 min 95% B; oven: 35° C.; flow rate: 0.0 min 1.0 ml/min→3.0 min 3.0ml/min→4.0 min 3.0 ml/min; UV detection: 210 nm.

Method 10 (LC-MS)

Instrument: Micromass Platform LCZ with HPLC Agilent series 1100;column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; eluent A: 1 l ofwater+1 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile+1ml of 50% strength formic acid; gradient: 0.0 min 100% A→0.2 min 100%A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate:0.8 ml/min; UV detection: 210 nm.

Method 11 (LC-MS)

MS apparatus type: Micromass ZQ; HPLC apparatus type: Waters Alliance2790; column: Grom-Sil 120 ODS-4 HE, 50 mm×2 mm, 3.0 μm; eluent A: 1l ofwater+500 μl of 50% strength formic acid; eluent B: 1 l ofacetonitrile+500 μl of 50% strength formic acid; gradient: 0.0 mm 0%B→0.2 min 0% B→2.9 min 70% B→3.1 min 90% B→4.5 min 90% B; oven: 45° C.;flow rate: 0.8 ml/min; UV detection: 210 nm.

Method 12 (HPLC)

Instrument: HP 1100 with DAD; column: Kromasil 100 RP-18, 125 mm×4 mm, 5μm; eluent A: 1 l of water+4 vials PIC B7, eluent B: acetonitrile;gradient: 0.0 min 2% B, 1.0 min 2% B, 9.0 min 90% B, 13 min 90% B, 13.5min 2% B, 15.5 min 2% B; flow rate: 2 ml/min; oven: 30° C.; UVdetection: 210 nm. (PIC B7: heptanesulphonic acid from Millipore/WatersCorp.)

Method 13 (LC-MS)

Instrument: Micromass Platform LCZ with HPLC Agilent series 1100;column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; eluent A: 1 l ofwater+1 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile+1ml of 50% strength formic acid; gradient: 0.0 min 100% A→0.2 min 100%A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate:0.8 ml/min; UV detection: 208-400 nm.

Method 14 (LC-MS)

Instrument: Micromass Quattro LCZ, with HPLC Agilent series 1100;column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; eluent A: 1 l ofwater+1 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile+1ml of 50% strength formic acid; gradient: 0.0 min 100% A→0.2 min 100%A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C.; flow rate:0.8 ml/min; UV detection: 208-400 nm.

Starting Compounds

Example I Methyl 3-[4-(4-phenoxybutoxy)phenyl]propanoate

A solution of 10.0 g of methyl 3-(4-hydroxyphenyl)propanoate and 12.7 gof 4-phenoxy-1-butyl bromide in 100 ml of acetonitrile is mixed with11.5 g of potassium carbonate and heated to reflux for 15 hours. Thesolvent is then removed in a rotary evaporator, and the residue is takenup in ethyl acetate and water. After phase separation, the aqueous phaseis extracted with ethyl acetate. The combined organic phases are washedwith saturated sodium chloride solution and dried over anhydrous sodiumsulphate. The crude product after evaporation is purified by suctionfiltration through silica gel with cyclohexane/ethyl acetate 19:1. 12.6g of product are obtained.

TLC: R_(f): 0.36 (cyclohexane/ethyl acetate 1:1).

HPLC (method 1): R_(t): 5.41 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 7.32-7.23 (m, 2H), 7.11 (d, 2H),6.96-6.82 (m, 5H), 3.98 (m, 4H), 3.57 (s, 3H), 2.77 (t, 3H), 2.57 (t,2H), 1.85 (m, 4H).

MS (ESI+): m/z=329 (M+H⁺), 351 (M+Na⁺).

Example II 3-[4-(4-phenoxybutoxy)phenyl]-1-propanol

20.1 ml of a 1 molar solution of lithium aluminium hydride intetrahydrofuran is introduced. While stirring, a solution of 12.0 g ofmethyl 3-[4-(4-phenoxybutoxy)-phenyl]propanoate in 40 ml of THF is addeddropwise in such a way that the mixture just starts to boil. The mixtureis stirred at room temperature for 30 minutes. 1 ml of methanol iscautiously added to the suspension in order to hydrolyze excess lithiumaluminium hydride. The mixture is then added to 1 molar hydrochloricacid and extracted with ethyl acetate. The organic phase is separatedoff, washed with saturated sodium chloride solution and dried overanhydrous sodium sulphate. Filtration and evaporation result in 10.9 gof product.

HPLC (method 1): R_(t): 4.94 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.30-7.24 (m, 2H), 7.08 (d, 2H),6.95-6.88 (m, 3H), 6.83 (d, 2H), 4.39 (t, 1H), 4.01 (m, 4H), 3.38(quart, 2H), 2.53 (t, 2H), 1.83 (m, 4H), 1.67 (m, 2H).

MS (ESI+): m/z=301 (M+H⁺), 323 (M+Na⁺).

Example III 3-[4-(1,1′-Biphenyl-4-ylmethoxy)phenyl]-1-propanol

12.8 g (41.4 mmol) of 4-phenylbenzyl bromide, 6.94 g (45.6 mmol) of4-hydroxy-phenylpropanol and 6.87 g (49.7 mmol) of potassium carbonateare stirred in 50 ml of butyronitrile at 120° C. for 6 hours. Cooling toroom temperature is followed by removal of the inorganic salts byfiltration with suction and concentration in vacuo. The crude product ispurified by chromatography on silica gel 60 (mobile phase gradientcyclohexane-->cyclohexane/ethyl acetate 60:40). 4.90 g (37% of theory)of product are obtained.

m.p.: 128° C.

HPLC (method 1): R_(t): 5.12 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.70-7.64 (m, 4H), 7.55-7.42 (m, 4H),7.40-7.33 (m, 1H), 7.11 (d, 2H), 6.93 (d, 2H), 5.11 (s, 2H), 4.39 (t,1H), 3.39 (m, 2H), 2.53 (m, 21, 1.67 (quint, 2H).

MS (DCI): m/z=336 (M+NH₄ ⁺).

Example IV 1-(3-Bromopropyl)-4-(4-phenoxybutoxy)benzene

10.0 g of 3-[4-(4-phenoxybutoxy)phenyl]-1-propanol are dissolved in 50ml of tetrahydrofuran, and 10.5 g of solid triphenylphosphine are added.13.2 g of solid tetrabromomethane are added to the solution. After about5 minutes, the mixture starts to become cloudy. The reaction is completeafter one hour. The precipitate is filtered off, and the filtrate isconcentrated. The crude product is purified by suction filtration onsilica gel with cyclohexane/ethyl acetate 15:1 as mobile phase. 8.5 g ofproduct are obtained.

HPLC (method 1): R_(t): 6.01 min.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm) 7.29-7.24 (m, 2H), 7.12 (d, 2H),6.94-6.89 (m, 3H), 6.86 (d, 2H), 4.00 (m, 4H), 3.48 (t, 2H), 2.63 (t,2H), 2.05 (m, 2H), 1.84 (m, 4H).

MS (DCI, NH₃): m/z=380/382 (M+NH₄ ⁺).

Example V 4-{[4-(3-Bromopropyl)phenoxy]methyl}-1,1′-biphenyl

4-{[4-(3-Bromopropyl)phenoxy]methyl}-1,1′-biphenyl is obtained inanalogy to the process described in Example IV by bromination of3-[4-(1,1′-biphenyl-4-yl-methoxy)phenyl]-1-propanol.

HPLC (method 1): R_(t): 6.10 min

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.70-7.64 (m, 4H), 7.55-7.43 (m, 4H),7.40-7.33 (m, 1H), 7.14 (d, 2H), 6.96 (d, 2H), 5.12 (s, 2H), 3.48 (t,2H), 2.64 (t, 2H), 2.05 (quint, 2H).

MS (DCI): m/z=400 (M+NH₄ ⁺).

Example VI 3-[4-(4-phenoxybutoxy)phenyl]propanoic acid

100 ml of methanol and 100 ml of 2 molar sodium hydroxide solution areadded to a solution of 10 g of methyl3-[4-(4-phenoxybutoxy)phenyl]propanoate in 100 ml of tetrahydrofuran.The mixture is heated at 60° C. for two hours. It is then acidified with2 molar hydrochloric acid, and most of the organic solvent is removed ina rotary evaporator. A precipitate separates out and is filtered offwith suction and washed with water at room temperature. 7.7 g of productare obtained.

HPLC (method 1): R_(t): 4.77 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.10 (s, broad, 1H), 7.32-7.23 (m,2H), 7.12 (d, 2H), 6.95-6.81 (m, 5H), 4.00 (m, 4H), 2.73 (t, 2H), 2.48(t, 2H), 1.85 (m, 4H).

MS (DCI, NH₃): m/z=332.2 (M+NH₄ ⁺).

Example VII 3-[4-(4-phenoxybutoxy)phenyl]propanoyl chloride

A suspension of 250 mg of 3-[4-(4-phenoxybutoxy)phenyl]propanoic acid in10 ml of chloroform is heated to about 40° C. A solution is formedthereby. 1.4 ml of oxalyl chloride are added (evolution of gas). Themixture is heated to reflux. After two hours, the mixture is evaporatedto dryness and the product is dried under high vacuum. 264 mg of productare obtained.

MS (DCI, NH₃): m/z=350/352 (M+NH₄ ⁺).

Example VIII 5-(Methoxycarbonyl)-2-nitrobenzoic acid

A solution of 320 mg of sodium dihydrogen phosphate in 10 ml of waterand 1 ml of hydrogen peroxide (35% strength) is added to a solution 2.0g of methyl 3-formyl-4-nitrobenzoate [M. G. Vetelino et al., tetrahedronLett. 35, 219-222 (1994).] in 20 ml of acetonitrile at 10° C. A solutionof 1.5 g of sodium chlorite in 10 ml of water is then added dropwiseover the course of 15 minutes. The mixture is then stirred at 10° C. fora further 2 hours. The reaction is stopped by adding 400 mg of sodiumsulphite. The mixture is diluted with 2 molar hydrochloric acid andextracted with ethyl acetate. The organic extract is washed withsaturated sodium chloride solution and dried over anhydrous sodiumsulphate. Filtration and evaporation result in 225 mg of product.

HPLC (method 1): R_(t): 3.68 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 14.22 (s broad, 1H), 8.34 (d, 1H);8.29 (dd, 1H), 8.09 (d, 1H), 3.92 (s, 3H).

MS (DCI, NH₃): m/z=243 (M+NH₄ ⁺), 260 (M+N₂H₇ ⁺).

Example IX Methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate

Method 1:

10 g of 3-aminocyclohexane-1-carboxylic acid hydrochloride are stirredtogether with 15.5 ml of trimethylsilyl chloride in 55 ml of methanol atroom temperature overnight. Subsequent removal of the solvent and allother volatile components in the rotary evaporator results in 8 g ofmethyl 3-aminocyclohexane-1-carboxylate hydrochloride. 8.0 g of methyl3-aminocyclohexane-1-carboxylate hydrochloride, 14.4 g ofN-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (ETLC),5.1 g of 1-hydroxy-1H-benzotriazole hydrate (HOBT) and 11 ml oftriethylamine are added successively to a solution of 7.37 g of2-hydroxy-5-carbomethoxybenzoic acid [CAS No. 79128-78-2] in 1000 ml ofdichloromethane. After 15 hours at room temperture, 250 ml of water areadded to the reaction mixture. After phase separation, the aqueous phaseis extracted with ethyl acetate. The combined dichloromethane and ethylacetate phases are washed with saturated sodium chloride solution anddried over anhydrous sodium sulphate. Filtration and concentrationresult in an oil which is initially prepurified by suction filtrationthrough silica gel with cyclohexane/ethyl acetate 4:1 as mobile phase.The product obtained in this way contains a mixture of all four possiblestereoisomers: cis racemate and trans racemate. Most of one of the tworacemates is removed by crystallization from cyclohexane and mixed withabout 5% ethyl acetate. This results in 4.18 g of product (racemate A).The product remaining after evaporation of the mother liquor isseparated by preparative HPLC on an achiral RP column. This results in afurther 0.2 g of the material of fraction 1, which is combined with thelatter. In addition, 1.55 g of the other racemate are obtained (racemateB).

Racemate A:

HPLC (method 1): R_(t): 4.50 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 13.34 (s broad, 1H), 8.92 (d broad,1H), 8.57 (d, 1H), 7.97 (dd, 1H), 6.99 (d, 1H), 3.88 (m, 1H), 3.83 (s,3H), 3.60 (s, 3H), 2.49 (m, 1H), 2.07 (m, 1H), 1.92-1.78 (m, 3H),1.56-1.15 (m, 4H).

MS (DCI, NH₃): m/z=336.1 (M+H⁺), 353 (M+NH₄ ⁺).

Racemate B:

HPLC (method 1): R_(t): 4.42 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 13.13 (s broad, 1H), 8.76 (d broad,1H), 8.53 (d, 1H), 7.97 (dd, 1H), 7.00 (d, 1H), 4.12 (m, 1H), 3.83 (s,3H), 3.62 (s, 3H), 2.82 (m, 1H), 1.93 (m, 1H), 1.83-1.45 (m, 7H).

MS (DCI, NH₃): m/z 336.1 (M+H+), 353 (M+NH₄ ⁺).

Method 2:

Racemate B can be resolved into its optical antipodes by chromatographyon a preparative scale.

Method: Chiral silica gel selector KBD 8361 (particle size 10 μm) basedon the selector poly(N-methacryloyl-L-leucine 1-menthylamide); column:420 mm×100 mm; 9:1 (vol/vol) tert-butyl methyl ether/ethyl acetatemixture as eluent; flow rate: 100 ml/min; UV detection: 254 nm; sample:10 g dissolved in 1000 ml of eluent; sample loaded: 80 ml; temperature:24° C.

(+) Enantiomer of racemate B [(+) Benantiomer]:

HPLC (KBD 8361 column as above, 250 mm×20 mm, isohexane/ethyl acetate4:1, flow rate: 25 ml/min, WV detection: 280 nm, 24° C.): R_(t): 15.8min.

Specific rotation (methanol, 589 nm, 20° C.): +36.8°.

(−) Enantiomer of racemate B [(−) Benantiomer]:

HPLC (KBD 8361 column as above, 250 mm×20 mm, isohexane/ethyl acetate4:1, flow rate: 25 ml/min, UV detection: 280 nm, 24° C.): R_(t): 9.6min.

Specific rotation (methanol, 589 nm, 20° C.): −37.60.

Method 3:

Racemate B can also be obtained specifically in the following way:

21.8 ml of thionyl chloride are added dropwise to a solution of 5.85 gof 2-hydroxy-5-(methoxycarbonyl)benzoic acid in 128 ml of anhydrous THFat 0° C. The reaction mixture is left to stir at room temperatureovernight. The solvent and excess thionyl chloride are then completelyremoved in a rotary evaporator. The remaining residue is taken up 120 mlof anhydrous dichloromethane, and 5.5 g of methyltrans-3-aminocyclohexanecarboxylate hydrochloride and, at −20° C., 10.4ml of triethylamine are added. The reaction mixture is then allowed toreach room temperature and is stirred at this temperature for a further1.5 hours. Then about 50 ml of 0.01 molar hydrochloric acid are added.After phase separation, the aqueous phase is extracted twice more withethyl acetate. The combined organic extracts are dried over anhydroussodium sulphate. Filtration and evaporation are carried out. The productis purified by suction filtration through silica gel withcyclohexane/ethyl acetate 4:1 as mobile phase. 4.06 g of product areobtained. The product consists of 87% racemate B and 13% racemate A.Further purification can take place as described in Example IX, method1.

Example X Methyl1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate

Method 1:

Methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylateis prepared in analogy to the process described in Example IX, method 1,from 2-hydroxy-5-carbomethoxybenzoic acid [CAS No. 79128-78-2] andmethyl piperidine-4-carboxylate hydrochloride.

HPLC (method 1): R_(t): 3.64 min.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 10.78 (s, 1H), 7.83 (dd, 1H), 7.69 (d,1H), 7.96 (d, 1H), 4.37 (broad, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 3.36(broad, 1H), 2.98 (m broad, 21), 2.63 (m, 1H), 1.83 (m, 2H), 1.50 (m,2H).

MS (DCI, NH₃): m/z=322 (M+H⁺), 339 (M+NH₄ ⁺).

Method 2:

37 ml of thionyl chloride are added dropwise to a solution of 10.0 g of2-hydroxy-5-carbomethoxybenzoic acid in 600 ml of THF at a temperatureof about 0° C. The mixture is allowed to reach room temperature and isstirred for 15 hours. The mixture is then completely evaporated in arotary evaporator. The remaining oil is dissolved in 400 ml of anhydrousdichloromethane. Then, at about −20° C., 11 ml of triethylamine and 8.76g of methyl isonipecotate are added. The reaction mixture is allowed toreach room temperature. After two hours it is acidified with 0.1 molarhydrochloric acid (pH about 3) and extracted with ethyl acetate. Theorganic extract is washed successively with water and saturated sodiumchloride solution. Drying over anhydrous sodium sulphate, filtration,evaporation. The crude product is initially prepurified by suctionfiltration through silica gel with cyclohexane/ethyl acetate 1:1 asmobile phase. The product-containg fractions are combined andevaporated, and the resulting residue is triturated with a little ethylacetate. 13.4 g of a solid are obtained.

Example XI Methyl1-[5-(methoxycarbonyl)-2-nitrobenzoyl]-4-piperidinecarboxylate

Methyl 1-[5-(methoxycarbonyl)-2-nitrobenzoyl]-4-piperidinecarboxylate isprepared in analogy to the process described in Example IX from5-(methoxycarbonyl)-2-nitrobenzoic acid and methylpiperidine-4-carboxylate hydrochloride.

TLC: R_(f): 0.21 (cyclohexane/ethyl acetate 1:1).

HPLC (method 1): R_(t): 3.96 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 8.32 (d, 1H), 8.19 (dd, 1H), 8.00 (d,1H), 4.34 (m, 1H), 3.92 (s; 3H), 3.62 (s, 3H), 3.18-2.94 (m, 2H),2.77-2.63 (m, 1H), 1.97 (m, 1H), 1.80-1.48 (m, 4H).

Example XII Methyl1-[2-amino-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate

A solution of 600 mg of methyl1-[5-(methoxycarbonyl)-2-nitrobenzoyl]-4-piperidinecarboxylate in 200 mlof methanol is mixed with a spatula tip of palladium (10% on activatedcarbon) and hydrogenated in a Parr apparatus under a pressure of 3.5 barof hydrogen at room temperature. After three hours, the reaction mixtureis filtered through a little silica gel and evaporated. 474 mg ofproduct are obtained.

HPLC (method 1): R_(t): 3.68 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.67 (dd, 1H), 7.57 (d, 1H), 6.72 (d,1H), 5.98 (s broad, 2H), 3.82 (m, 1H), 3.76 (s, 3H), 3.62 (s, 3H), 3.02(m, 2H), 2.63 (m, 1H), 1.85 (m, 2H), 1.63-1.48 (m, 3H).

MS (DCI, NH₃): m/z=321.2 (M+H⁺), 338 (M+NH₄ ⁺).

Example XIII Ethyl3-formyl-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate

1.37 g (3.76 mmol) of 1-(3-bromopropyl)-4-(4-phenoxybutoxy)benzene, 0.79g (3.76 mmol) of ethyl 3-formyl-4-hydroxybenzoate [CAS No. 82304-99-2]and 0.78 g (5.64 mmol) of potassium carbonate are dissolved in 20 ml ofDMF, and the mixture is stirred at 40° C. for 16 hours. It is thenconcentrated, and the residue is taken up in 200 ml of water andextracted with dichloromethane (three times 100 ml). The combinedorganic phases are dried (sodium sulphate) and concentrated, and thecrude product is purified by chromatography on silica gel (mobile phasegradient cyclohexane-->cyclohexane/ethyl acetate 5:1). 1.45 g of productare obtained.

HPLC (method 2): R_(t): 5.62 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 10.48 (s, 1H), 8.49 (s, 1H), 8.20 (dd,1H), 7.29-7.23 (m, 2H), 7.12-7.06 (d, 2H), 6.98-6.80 (m, 6H), 4.36 (q,2H), 4.13 (t, 2H), 4.07-3.96 (m, 4H), 2.78 (t, 2H), 2.17 (quint, 2H),1.97 (m, 4H), 1.38 (t, 3H).

MS (ESI+): m/z=477 (M+H⁺).

Example XIV Ethyl4-{₃-[₄-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-3-formylbenzoate

Preparation takes place in analogy to Example XIII from1,1′-biphenyl-4-ylmethyl 4-(3-bromopropyl)phenyl ether and ethyl3-formyl-4-hydroxybenzoate.

HPLC (method 2): R_(t): 6.04 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 10.33 (s, 1H), 8.86 (d, 1H), 8.22 (dd,1H), 7.65-7.55 (m, 4H), 7.53-7.34 (m, 5H), 7.16-6.90 (m, 5H), 5.08 (s,2H), 4.38 (q, 2H), 4.29 (t, 2H), 2.80 (t, 2H), 2.24 (quint, 2H), 1.39(t, 3H).

MS (DCI): m/z 512 (M+NH₄ ⁺).

Example XV2-{3-[4-(1,1′-Biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoicacid

3.10 g (6.28 mmol) of ethyl4-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-3-formylbenzoate areintroduced into 50 ml of THF. At about 0° C. (internal temperature),solutions of 2.13 g (18.8 nmol) of sodium chlorite in 2.5 ml of waterand 1.83 g (18.8 mmol) of sulphamic acid in 9 ml of water aresimultaneously added dropwise. The mixture is then stirred at 0° C. for15 minutes. The reaction mixture is added to 120 ml of water andextracted with ethyl acetate (four times 60 ml). The combined organicphases are washed with saturated sodium chloride solution (twice 50 ml).A finely dispersed precipitate is evident in the organic phase. 300 mlof dichloromethane are added, and the solution is dried over sodiumsulphate and concentrated. The resulting product (2.96 g) is reactedwithout further purification.

HPLC (method 2): R_(t): 6.13 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 8.86 (d, 1H), 8.22 (dd, 1H), 7.64-7.55(m, 4H), 7.53-7.33 (m, 5H), 7.15-6.92 (m, 5), 5.08 (s, 2H), 4.38 (q,2H), 4.29 (t, 2H), 2.80 (t, 2H), 2.24 (quint., 2H), 1.39 (t, 3H).

LC-MS (method 3): R_(t): 4.99 min.

MS (ESI+): m/z=511 (M+H⁺).

Example XVI5-(Ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoic acid

Preparation takes place in analogy to Example XV from ethyl3-formyl-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 10.46 (s, broad, 1H), 8.85 (d, 1H), 8.22(dd, 1H), 7.32-7.21 (m, 3H), 7.12-6.80 (m, 7H), 4.38 (q, 2H), 4.28 (t,2H), 4.08-3.97 (m, 4H), 2.78 (t, 2H), 2.24 (quint, 2H), 1.97 (m, 4H),1.39 (t, 3H).

LC-MS (method 3): R_(t): 4.20 min.

MS (ESI+): m/z=493 (M+H⁺).

Example XVII Methyl 3-[4-(3-cyclohexylpropoxy)phenyl]propanoate

69.9 g of caesium carbonate are added to a solution of 32.21 g of methyl3-(4-hydroxyphenyl)propanoate and 44.0 g 1-bromo-3-cyclohexylpropane in100 ml of anhydrous DMF, and the mixture is stirred at a temperature of50° C. for 6 hours. The reaction mixture is then poured into about 800ml of water and, after addition of 12.3 ml of glacial acetic acid,extracted three times with ethyl acetate. The combined organic extractsare washed successively with water and saturated sodium chloridesolution. After drying over anhydrous sodium sulphate, the solvent isremoved in a rotary evaporator. The product is purified by suctionfiltration on silica gel with cyclohexane/ethyl acetate 20:1 as mobilephase. 51.52 g of product are obtained.

TLC: R_(f): 0.47 (cyclohexane/ethyl acetate 1:1).

HPLC (method 2): R_(t): 6.09 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.10 (d, 2H), 6.81 (d, 2H), 3.88 (t,2H), 3.57 (s, 3H), 2.77 (t, 2H), 2.57 (t, 2H), 1.72-1.64 (m, 7H),1.37-1.09 (m, 6H), 0.93-0.81 (m, 2H).

MS (DCI, NH₃): M/Z=321.9 (M+NH₄ ⁺).

Example XVIII 3-[4-(3-Cyclohexylpropoxy)phenyl]propan-1-ol

3-[4-(3-Cyclohexylpropoxy)phenyl]propan-1-ol is obtained in analogy tothe process described in Example II by reduction of methyl3-[4-(3-cyclohexylpropoxy)phenyl]-propanoate with lithium aluminiumhydride.

TLC: R_(f): 0.30 (cyclohexane/ethyl acetate 1:1).

HPLC (method 1): R_(t): 5.60 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.08 (d, 2H), 6.80 (d, 2H), 4.38 (t,1H), 3.88 (t, 2H), 3.39 (quart., 2H), 2.51 (t, 2H), 1.71-1.61 (m, 9H),1.32-1.12 (m, 6H), 0.93-0.81 (m, 2H).

MS (DCI, NH₃): m/z=394.1 (M+NH₄ ⁺).

Example XIX 1-(3-Bromopropyl)-4-(3-cyclohexylpropoxy)benzene

1-(3-Bromopropyl)-4-(3-cyclohexylpropoxy)benzene is obtained in analogyto the process described in Example IV from3-[4-(3-cyclohexylpropoxy)phenyl]propan-1-ol bromination withtriphenylphosphine and tetrabromomethane.

TLC: R_(f): 0.69 (cyclohexane/ethyl acetate 1:1).

HPLC (method 4): R_(t): 7.27 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.10 (d, 2H), 6.82 (d, 2H), 3.89 (t,2H), 3.48 (t, 2H), 2.62 (t, 2H), 2.03 (quint., 2H), 1.73-1.60 (m, 7H),1.30-1.12 (m, 6H), 0.93-0.81 (m, 2H).

MS (DCI, NH₃): m/z=338 and 340 (M⁺), 356 and 358 (M+NH₄ ⁺).

Example XX 3-[4-(3-Cyclohexylpropoxy)phenyl]propyl methanesulphonate

43.3 g of diisopropylethylamine and 25.6 g of methanesulphonyl chlorideare added to a solution of 30.89 g of3-[4-(3-cyclohexylpropoxy)phenyl]propan-1-ol in 250 ml of anhydrous THFat 0° C. The mixture is left to stir at room temperature for one hour.Then 50 ml each of water and ethyl acetate are added. The phases areseparated and the organic phase is washed successively with water andsaturated sodium chloride solution. After drying over anhydrousmagnesium sulphate, the solvent is removed in a rotary evaporator. Theresidue is triturated with petroleum ether. Filtration with suction anddrying results in 37.8 g of product.

HPLC (method 5): R_(t): 5.57 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 7.08 (d, 2H), 6.83 (d, 2H), 4.22 (t,2H), 3.90 (t, 2H), 3.01 (s, 3H), 2.70 (t, 2H), 2.04 (d quart., 2H),1.89-0.78 (m, 15H).

MS (DCI, NH₃): m/z 372.2 (M+NH₄ ⁺).

Example XXI Methyl 3-{4-[4-(cyclohexyloxy)butoxy]phenyl}propanoate

Methyl 3-{4-[4-(cyclohexyloxy)butoxy]phenyl}propanoate is obtained inanalogy to the process described in Example I by alkylation of methyl3-(4-hydroxyphenyl)-propanoate with (4-bromobutoxy)cyclohexane.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 7.09 (d, 2H), 6.82 (d, 2H), 3.94 (t,2H), 3.67 (s, 3H), 3.49 (t, 2H), 3.30-3.15 (m, 1H), 2.88 (t, 2H), 2.59(t., 2H), 1.94-1.17 (m, 14H).

LC-MS (method 6): R_(t): 3.01 min, m/z=335 (M+H⁺).

Example XXII 3-{4-[4-(Cyclohexyloxy)butoxy]phenyl}propan-1-ol

3-{4-[4-(Cyclohexyloxy)butoxy]phenyl}propan-1-ol is obtained in analogyto the process described in Example II by reduction of methyl3-{4-[4-(cyclohexyloxy)-butoxy]phenyl}propanoate with lithium aluminiumhydride.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.10 (d, 2M), 6.82 (d, 2H), 3.95 (t,2H), 3.67 (t, 2H), 3-49 (t, 2H), 3.23-3.19 (m, 1H), 2.63 (t, 2H),1.92-1.20 (16H).

LC-MS (method 6): R_(t): 2.67 min, m/z 307 (M+H⁺).

Example XXIII 1-(3-Bromopropyl)-4-[4-(cyclohexyloxy)butoxy]benzene

1-(3-Bromopropyl)-4-[4-(cyclohexyloxy)butoxy]benzene is obtained inanalogy to the process described in Example IV by bromination of3-{4-[4-(cyclohexyloxy)-butoxy]phenyl}propan-1-ol withtriphenylphosphine and tetrabromomethane.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.09 (d, 2H), 6.82 (d, 2H), 3.97 (t,2H), 3.50 (t, 2H), 3.38 (t, 2H), 3.23-3.18 (m, 1H), 2.71 (t, 2H), 2.12(quint, 2H), 1.92-1.82 (m, 4H), 1.77-1.70 (m, 4H), 1.57-1.19 (6H).

MS (EI+): m/z=369 and 371 (M+H⁺).

Example XXIV Methyl 3-{4-[(4-isopropoxybenzyl)oxy]phenyl}propanoate

A solution of 11.0 g of 4-isopropoxybenzyl chloride and 10.7 g of methyl3-(4-hydroxyphenyl)propanoate in 120 ml of butyronitrile is mixed with12.4 g of potassium carbonate and heated to reflux for 15 hours. Thesolvent is then distilled out in a rotary evaporator. The residue istaken up in ethyl acetate and washed successively with water andsaturated sodium chloride solution. After drying over sodium sulphate,the organic phase is evaporated and the product is purified by suctionfiltration through silica gel with cyclohexane/ethyl acetate 9:1. 9.4 gof product are obtained.

HPLC (method 1): R_(t): 5.33 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.32 (d, 2H), 7.11 (d, 2H), 6.90 (d,2H), 6.89 (d, 2H), 4.94 (s, 2H), 4.60 (sep, 1H), 3.57 (s, 3H), 2.78 (t,2H), 2.57 (t, 2H), 1.27 (d, 6H).

MS (DCI, NH₃): m/z 346.2 (M+NH₄ ⁺).

Example XXV 3-{4-[(4-Isopropoxybenzyl)oxy]phenyl}propan-1-ol

3-{4-[(4-Isopropoxybenzyl)oxy]phenyl}propan-1-ol is obtained in analogyto the process described in Example II by reduction of methyl3-{4-[(4-isopropoxybenzyl)-oxy]phenyl}propanoate with lithium aluminiumhydride.

TLC: R_(f): 0.48 (cyclohexane/ethyl acetate 1:1).

HPLC (method 1): R_(t): 4.87 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.32 (d, 2H), 7.11 (d, 2H), 6.90 (d,2H), 6.89 (d, 2H), 4.93 (s, 2H), 4.54 (sep, 1H), 3.68 (t broad, 2H),2.64 (t, 2H), 1.93-1.79 (m, 2H), 1.33 (d, 6H), 1.26 (s broad, 1H).

MS (DCI, NH₃): m/z=318 (M+NH₄ ⁺).

Example XXVI 1-(3-Bromopropyl)-4-[(4-isopropoxybenzyl)oxy]benzene

1-(3-Bromopropyl)-4-[(4-isopropoxybenzyl)oxy]benzene is obtained inanalogy to the process described in Example IV from3-{4-[(4-isopropoxybenzyl)oxy]phenyl}propan-1-ol by bromination withtriphenylphosphine and tetrabromomethane.

TLC: R_(f): 0.48 (cyclohexane/ethyl acetate 20:1).

HPLC (method 5): R_(t): 4.87 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.32 (d, 2H), 7.10 (d, 2H), 6.90 (d,2H), 6.89 (d, 2H), 4.94 (s, 2H), 4.53 (sep, 1H), 3.38 (t, 2H), 2.71 (t,2H), 2.12 (pent, 2H), 1.33 (d, 6H).

MS (DCI, NH₃): M/Z=380 and 382 (M+NH₄ ⁺).

Example XXVII Methyl 4-(cyclopropylmethoxy)benzoate

A solution of 3.0 g of methyl 4-hydroxybenzoate and 2.93 g ofcyclopropylmethyl bromide in 60 ml of anhydrous acetonitrile is mixedwith 3.27 g of potassium carbonate and heated to reflux for 15 hours.The solvent is then removed in a rotary evaporator. The residue is takenup in ethyl acetate and washed successively with water and saturatedsodium chloride solution. Drying over solid sodium sulphate is followedby evaporation to dryness. The product is purified by suction filtrationthrough silica gel with cyclohexane/ethyl acetate 5:1 as mobile phase.4.0 g of a solid are obtained.

TLC: R_(f): 0.29 (cyclohexane/ethyl acetate 5:1).

HPLC (method 1): R_(t): 4.77 min.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.89 (d, 2H), 7.02 (d, 21), 3.90 (d,2H), 3.81 (s, 3H), 1.28-1.19 (m, 1H), 0.61-0.57 (m, 2H), 0.36-0.32 (m,2M).

MS (DCI, NH₃): m/z=207.1 (M+H⁺), 224.1 (M+NH₄ ⁺).

Example XXVIII [4-(Cyclopropylmethoxy)phenyl]methanol

[4-(Cyclopropylmethoxy)phenyl]methanol is obtained analogously to theprocess described in Example II by reduction of methyl4-(cyclopropylmethoxy)-benzoate with lithium aluminium hydride.

TLC: R_(f): 0.38 (cyclohexane/ethyl acetate 1:1).

HPLC (method 1): R_(t): 3.91 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.20 (d, 2H), 6.86 (d, 2H), 4.98 (t,1H), 4.40 (d, 2H), 3.78 (d, 2H), 1.27-1.12 (m, 1H), 0.58-0.52 (m, 2H),0.32-0.27 (m, 2H).

MS (DCI, NH₃): m/z 161 (M+H⁺), 178 (M+NH₄ ⁺), 195 (M+N₂H₇+).

Example XXIX 1-(Chloromethyl)-4-(cyclopropylmethoxy)benzene

2.54 g of [4-(cyclopropylmethoxy)phenyl]methanol are dissolved in 30 mlof anhydrous dichloromethane and, at room temperature, 1.56 ml ofthionyl chloride are added dropwise. After the addition is complete, themixture is left to stir at room temperature for 30 minutes. The mixtureis then evaporated to dryness in a rotary evaporator. 2.77 g of productare obtained.

TLC: R_(f): 0.60 (cyclohexane/ethyl acetate 5:1).

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.33 (d, 2H), 6.91 (d, 2H), 4.70 (s,2H), 3.81 (d, 2H), 1.28-1.13 (m, 1H), 0.59-0.52 (m, 2H), 0.33-0.28 (m,2H).

MS (EI+): m/z=196 (M⁺).

Example XXX 1-(Chloromethyl)-2-isopropoxybenzene

1-(Chloromethyl)-2-isopropoxybenzene is obtained in analogy to theprocess described in Example XXIX from (2-isopropoxyphenyl)methanol byreaction with thionyl chloride. The product is purified by vacuumdistillation.

b.p. 54° C. (0.16 mbar).

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 7.38 (d, 1H), 7.29 (d, 1H), 7.05 (d,1H), 6.91 (t, 1H), 4.68 (s, 2H), 4.67 (hep, 1H), 1.29 (d, 6H).

Example XXXI [(4-Bromobutoxy)methyl]cyclopropane

2.8 g of a 60% suspension of sodium hydride in mineral oil are added inportions to a solution of 5.0 g of hydroxymethylcyclopropane in 25 ml oftoluene at room temperature. The mixture is then heated at 100° C. for 2hours. After this, it is allowed to reach room temperature and asolution of 14.9 g of 1,4-dibromobutane in 15 ml of toluene is added.The mixture is left to stir at 100° C. for a further 15 hours. Then, atroom temperature, 10 ml of water are added, the phases are separated,and the toluene is removed in a rotary evaporator. The product isisolated by vacuum distillation.

b.p. 58-63° C. (0.56 mbar).

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 3.53 (t, 2H), 3.38 (t, 2H), 3.18 (d,2H), 1.89-1.79 (m, 2H), 1.63-1.54 (m, 2H), 1.02-0.91 (m, 1H), 0.47-0.41(m, 2H), 0.14-0.10 (m, 2H).

Example XXXII Methyl cis-3-hydroxycyclohexanecarboxylate

A total of 2.51 g of solid sodium borohydride is added in portions to asolution of 20.7 g of methyl 3-oxocyclohexanecarboxylate in 520 ml ofmethanol at a temperature of −78° C. After 2.5 hours at −78° C., 5 ml ofwater are added, and the reaction mixture is allowed to reach roomtemperature. The solvent is then removed in a rotary evaporator. Ethylacetate/water extraction is carried out. Drying of the organic phaseover anhydrous sodium sulphate, filtration and removal of ethyl acetateresult in 19.0 g of an oil. According to NMR, the product consists of amixture of two diastereomers in the ratio 94:6. In analogy to similarsodium borohydride reductions described in the literature forcyclohexanones substituted in position 3, it is concluded that the mainproduct must be the cis isomer.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm, main isomer): 4.60 (d, 1H), 3.58 (s,3H), 3.43-3.32 (m, 1H), 2.32 (tt, 1H), 2.03-1.97 (m, 1H), 1.82-1.67 (in,3H), 1.31-0.96 (m, 4H).

MS (DCI, NH₃): m/z=159 (M+H⁺), 176 (M+NH₄ ⁺).

Example XXXIII Methylcis-3-{[(4-methylphenyl)sulphonyl]oxy}cyclohexanecarboxylate

32 g of para-toluenesulphonyl chloride are added to a solution of 18.97g of methyl cis-3-hydroxycyclohexanecarboxylate and 97 ml of pyridine in410 ml of anhydrous dichlormethane at a temperature of 0° C. The coolingbath is removed and the reaction mixture is left to stir at roomtemperature overnight. The solvent and excess pyridine are then removedin a rotary evaporator. The residue resulting from this is taken up inethyl acetate. Insolubles are removed by filtration and the filtrate isconcentrated. The solid residue is stirred a total of six times withapprox. 500 ml of petroleum ether each time. This results in 29.7 g of asolid.

HPLC (method 1): R_(t): 4.67 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.79 (d, 2H), 7.48 (d, 2H), 4.53-4.44(m, 1H), 3.57 (s, 3H), 2.42 (s, 3H), 2.07-1.99 (m, 1H), 1.78-1.69 (m,3H), 1.49 (quart., 1H), 1.41-1.13 (m, 3H).

MS (DCI, NH₃): m/z=330 (M+NH₄ ⁺).

Example XXXIV -Methyl trans-3-azidocyclohexanecarboxylate

A solution of 29.6 g of methylcis-3-{[(4-methylphenyl)sulphonyl]oxy}cyclohexanecarboxylate in 660 mlof DMF is mixed with 6.49 g of sodium azide and stirred at 80° C. for 15hours. At room temperature, 1000 ml of water are added and the productis extracted three times with approx. 300 ml of diethyl ether each time.The organic extract is washed with saturated sodium chloride solutionand dried over anhydrous sodium sulphate. Filtration and evaporation atroom temperature results in 16.8 g of an oil. The assignment of theproduct to the trans isomer results from experience that reactions ofthis type take place with inversion of the stereochemistry at thereaction site.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 3.94 (quint., 1H), 3.60 (s, 3H),2.68-2.56 (m, 1H), 1.82-1.72 (m, 3H), 1.62-1.43 (m, 5H).

MS (DCI, NH₃): m/z=201 (M+NH₄ ⁺), 218 (M+N₂H₇ ⁺).

Example XXXV Methyl trans-3-aminocyclohexanecarboxylate hydrochloride

Method 1:

A solution of 16.45 g of methyl trans-3-azidocyclohexancarboxylate in502 ml of methanol is initially mixed with 1.68 g of 10% palladium oncarbon and 17.29 g of ammonium formate and then heated to reflux for 1hour. It is then filtered through a little Tonsil and evaporated. Theresidue is dissolved in a little ethyl acetate, and 30 ml of a 4 molarsolution of hydrogen chloride in dioxane are added. After 20 minutes,the mixture is evaporated to dryness. 16.3 g of a solid are obtained.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.23 (s broad, 3H), 3.61 (s, 3H),3.07-3.00 (m, 1H), 2.51-2.42 (m, 1H), 2.17 (d broad, 1H), 1.93-1.74 (m,3H), 1.42-1.11 (m, 4H).

MS (DCI, NH₃): m/Z=158 (M+H⁺).

Method 2:

Methyl trans-3-aminocyclohexanecarboxylate hydrochloride can also beobtained by the method described in Example XXXV, method 1, from methyltrans-3-azido-cyclohex-4-enecarboxylate. In this case, merely the amountof ammonium formate employed is doubled.

Example XXXVI trans-3-Azidocyclohex-4-enecarboxylic acid

A solution of 10.6 g of sodium azide in 70 ml of water is added to asolution of 18.4 g of racemic cis-6-oxabicyclo[3.2.1]oct-3-en-7-one in175 ml of THF. The reaction mixture is then heated to reflux for 15hours. The THF is subsequently stripped off in a rotary evaporator at abath temperature of 30° C. The remaining aqueous phase is mixed with 165ml of 2 molar sodium hydroxide solution and extracted twice with 110 mlof toluene each time and once with diethyl ether. The aqueous phase isthen acidified with concentrated hydrochloric acid at about 10° C. Theproduct is extracted with dichloromethane. The organic extract is driedover anhydrous sodium sulphate, filtered and concentrated. 19.7 g of anoil, which becomes solid under storage in a refrigerator, are obtained.Assignment of the product to the trans isomer results from theexperience that reactions of this type take place with inversion of thestereochemistry at the reaction site.

HPLC (method 1): R_(t): 3.62 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.38 (s, broad, 1H), 6.09-6.03 (m,1H), 5.82-5.77 (m, 1H), 4.14 (pseudo-d, 1H), 2.59-2.48 (m, 1H, partlycovered by DMSO signal), 2.37-2.28 (m, 1H), 2.18-2.07 (m, 1H), 2.01-1.96(m, 1H), 1.82-1.73 (m, 1H).

MS (ESI−): m/z=166 (M−H⁻), 333 (2M-H⁻).

Example XXXVII Methyl trans-3-azidocyclohex-4-enecarboxylate

32.6 ml of trimethylsilyl chloride are added dropwise to a solution of19.5 g of trans-3-azidocyclohex-4-enecarboxylic acid in 1.5 l ofanhydrous methanol at 0° C. After one hour at 0° C., the mixture isstirred at room temperature for a further hour. It is then evaporated todryness. 19.1 g of an oil are obtained.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.75.

HPLC (method 1): R_(t): 4.24 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 6.08-6.02 (m, 1H), 5.82-5.77 (m, 1H),4.17 (pseudo-d, 1H), 3.62 (s, 3H), 2.69-2.59 (m, 1H), 2.38-2.29 (m, 1H),2.20-2.08 (m, 1H), 2.02-1.94 (m, 1H), 1.85-1.76 (m, 1H).

MS (DCI, NH₃): m/Z=199 (M+NH₄ ⁺).

Example XXXVIII Methyl 3-{4-[(triisopropylsilyl)oxy]phenyl}propanoate

13 ml of triisopropylsilyl chloride are added to a solution of 10 g ofmethyl 3-(4-hydroxyphenyl)propanoate and 11.77 g of imidazole in 22 mlof DMF at room temperature. The mixture is left to stir at roomtemperature. After 15 hours, the mixture is poured into 200 ml of 5%strength aqueous sodium dihydrogen phosphate solution and extracted withethyl acetate. The organic phase is washed with water and saturatedsodium chloride solution. Drying over anhydrous sodium sulphate,filtration, evaporation. The crude product is purified by suctionfiltration on silica gel with cyclohexane/ethyl acetate 30:1. 19.38 g ofan oil are obtained.

TLC (cyclohexane/ethyl acetate 9:1): R_(f): 0.53.

HPLC (method 4): R_(t): 6.27 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 7.09 (d, 2H), 6.77 (d, 2H), 3.56 (s,3H), 2.78 (t, 2H), 2.58 (t, 2H), 1.28-1.13 (m, 3H), 1.05 (d, 18H).

MS (DCI, NH₃): m/z=354 (M+NH₄ ⁺).

Example XXXIX 3-{4-[(Triisopropylsilyl)oxy]phenyl}propan-1-ol

14.4 ml of a 1 molar solution of lithium aluminium hydride in THF areintroduced. While stirring, a solution of 19.22 g of methyl3-{4-[(triisopropylsilyl)-oxy]phenyl}propanoate in 58 ml of THF is addeddropwise in such a way that the mixture just starts to boil. After theaddition is complete, the mixture is left to stir at room temperaturefor 30 minutes. Then excess lithium aluminium hydride is hydrolyzed bycautious addition of 1 ml of methanol. The mixture is poured into 20%strength aqueous sodium potassium tartrate solution and extracted withethyl acetate. The organic phase is washed successively with water andsaturated sodium chloride solution. Drying over anhydrous sodiumsulphate. Filtration and evaporation are followed by purification of theproduct by MPLC on silica gel with cyclohexane/ethyl acetate 9:1 asmobile phase. 10.7 g of an oil are obtained.

TLC (cyclohexane/ethyl acetate 9:1): R_(f): 0.17.

HPLC (method 4): R_(t): 5.78 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.05 (d, 2H), 6.77 (d, 2H), 4.39 (t,1H), 3.38 (quart, 2H), 2.53 (t, 2H), 1.67 (m, 2H), 1.28-1.16 (m, 3H),1.05 (d, 18H).

MS (DCI, NH₃): m/z=326 (M+NH₄ ⁺), 634 (2M+NH₄ ⁺).

Example XL [4-(3-Bromopropyl)phenoxy](triisopropyl)silane

A solution of 16.85 g of 3-{4-[(triisopropylsilyl)oxy]phenyl}propan-1-olin 15 ml of THF is mixed with 17.19 g of triphenylphosphine. As soon asit has dissolved, 21.73 g of tetrabromomethane are added, and themixture is stirred at room temperature. The reaction mixture initiallyheats up somewhat during this, and after about 5 minutes a solid startsto separate out. After 2 hours, the precipitate which has separated outis filtered off and the solvent is removed in a rotary evaporator. Theresidue is purified by MPLC on silica gel with cyclohexane/ethyl acetate50:1 as mobile phase. 17.53 g of an oil are obtained.

TLC (cyclohexane/ethyl acetate 4:1): R_(f): 0.65.

HPLC (method 4): R_(t): 8.19 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.09 (d, 2H), 6.79 (d, 2H), 3.48 (t,2H), 2.63 (t, 2H), 2.07 (m, 2H), 1.28-1.17 (m, 3H), 1.07 (d, 18H).

MS (DCI, NH₃): m/z=388 and 390 (M+NH₄ ⁺).

Example XLI Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(triisopropyl-silyl)oxy]phenyl}propoxy)benzoate

A solution of 2.66 g of [4-(3-bromopropyl)phenoxy](triisopropyl)silaneand 2.40 g of the (+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclo-hexyl]amino}carbonyl)benzoate(see Example IX, method 2) in 100 ml of butyronitrile is admixed with1.19 g of potassium carbonate and stirred at a bath temperature of 120°C. for 16 hours. The solvent is then removed in a rotary evaporator, andthe residue is partitioned between ethyl acetate and aqueous sodiumdihydrogen phosphate solution. The organic phase is washed successivelywith water and saturated sodium chloride solution. Drying over anhydroussodium sulphate. Filtration and concentration are followed bypurification of the product by suction filtration on silica gel withcyclohexane/ethyl acetate 2:1 as mobile phase. 3.91 g of an oil areobtained.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.51.

HPLC (method 4): R_(t): 7.14 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.21 (d, 1H), 8.08 (d broad, 1H), 8.01(dd, 1H), 7.21 (d, 1H), 7.09 (d, 2H), 6.78 (d, 2H), 4.14 (pseudo-t, 3H),3.82 (s, 3H), 3.57 (s, 3H), 2.70 (pseudo-t, 3H), 2.07 (m, 2H), 1.82 (m,2H), 1.70-1.48 (m, 6H), 1.27-1.17 (m, 3H), 1.05 (d, 18H).

MS (DCI, NH₃): m/z=626 (M+H⁺), 643 (M+NH₄ ⁺).

Example XLII Methyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]-amino}carbonyl)benzoate

6.5 ml of a 1 molar solution of tetra-n-butylammonium fluoride in THFare added to a solution of 3.90 g of methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(triisopropylsilyl)oxy]phenyl}propoxy)benzoatein 40 ml of THF at 0° C. The mixture is stirred at room temperature for10 minutes. The mixture is then evaporated to dryness, mixed withsaturated ammonium chloride solution and extracted with ethyl acetate.Drying over anhydrous sodium sulphate is followed by filtration andevaporation. The resulting crude product is purified by suctionfiltration on silica gel with cyclohexane/ethyl acetate 1:1 as mobilephase. 2.64 g of an oil are obtained.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.17.

HPLC (method 1): R_(t): 4.48 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 9.11 (s, 1H), 8.22 (d, 1H), 8.08 (dbroad, 1H), 8.01 (dd, 1H), 7.22 (d, 1H), 7.00 (d, 2H), 6.68 (d, 2H),4.13 (pseudo-t, 3H), 3.83 (s, 3H), 3.58 (s, 3H), 2.75-2.62 (m, 3H), 2.05(quint, 2H), 1.82 (m, 2H), 1.69-1.49 (m, 6H).

MS (DCI, NH₃): m/z=470 (M+H⁺), 487 (M+NH₄ ⁺).

Example XLIII Ethyl (2E)-3-{4-[5-phenoxypent-1-en-1-yl]phenyl}acrylate(E/Z mixture)

3.16 g of (4-phenoxybutyl)(triphenyl)phosphonium bromide are suspendedin 25 ml of THF under argon and cooled to −40° C. 2.36 ml ofn-butyllithium (1.6 molar in hexane) are added dropwise, and the mixtureis warmed to 0° C. after 5 minutes and cooled again to −40° C. after 15minutes. A solution of 0.70 g of ethyl 4-formylcinnamate in THF is addeddropwise and, after 5 minutes, the reaction mixture is warmed to roomtemperature. The solvent is removed in a rotary evaporator. 0.75 g ofproduct is obtained as an E/Z mixture.

HPLC (method 5): R_(t): 5.44 min.

LC-MS (method 8): R_(t): 4.0 min, m/z (EI+)=336.

Example XLIV (2E)-3-{4-[5-Phenoxypent-1-en-1-yl]phenyl}prop-2-en-1-ol(E/Z mixture)

A solution of 457 mg of ethyl(2E)-3-{4-[5-phenoxypent-1-en-1-yl]phenyl}acrylate (E/Z mixture) in 4 mlof toluene is cooled to −30° C., and 0.53 ml of a solution ofdiisobutylaluminium hydride (about 5.5 molar in hexane) is addeddropwise. After 30 minutes, the mixture is warmed to 0° C., saturatedammonium chloride solution is added, the mixture is extracted withdichloromethane, and the organic phase is dried over sodium sulphate.The solvent is removed in a rotary evaporator. 85 mg of product areobtained.

HPLC (method 5): R_(t): 4.91 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 7.40-7.19 (m, 6H), 6.98-6.83 (m, 3H),6.67-6.29 (m, 3H), 5.70 (dt, 1H), 4.33 (t 211), 3.98 (t, 2H), 2.55 (dq,2H), 2.05-1.86/m, 2H), 1.42 (t, 1H).

MS (DCI, NH₃): m/z=312 (M+NH₄ ⁺).

Example XLV 3-[4-(5-Phenoxypentyl)phenyl]propan-1-ol

About 5 mg of palladium on carbon (10%) are added to a solution of 98 mgof (2E)-3-{4-[5-phenoxypent-1-en-1-yl]phenyl}prop-2-en-1-ol in about 5ml of ethyl acetate, and the mixture is hydrogenated under 1 bar ofhydrogen at room temperature overnight. The mixture is filtered toremove catalyst and concentrated, and the residue is puriified on silicagel with cyclohexane/ethyl acetate 3:1. 53 mg of product are obtained.

HPLC (method 5): R_(t): 5.07 min.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.31-7.23 (m, 5M), 7.21-7.19 (m, 1H),6.96-6.86 (m, 3H), 3.95 (t, 2H), 3.68 (q, 2H), 2.68 (t, 2H), 2.62 (t,2H), 1.94-1.87 (m, 4H), 1.73-1.63 (m, 2H), 1.56-1.47 (m, 2H), 1.37-1.30(m, 1H).

LC-MS (method 9): R_(t): 2.72 min, m/z (EI+) 298.

Example XLVI 1-(3-Iodopropyl)-4-(5-phenoxypentyl)benzene

A solution of 53 mg of 3-[4-(5-phenoxypentyl)phenyl]propan-1-ol indiethyl ether/acetonitrile 3:1 is cooled to 0° C. and, under argon, 24mg of imidazole, 70 mg of triphenylphosphine and 68 mg of iodine areadded. The mixture is stirred for 30 minutes and the reaction is stoppedby adding concentrated sodium thiosulphate solution. The mixture isextracted with ethyl acetate, and the organic phase is washed withsaturated sodium chloride solution, dried over sodium sulphate andconcentrated. The residue is purified on silica gel withcyclohexane/ethyl acetate 40:1. 34 mg of product are obtained.

MS (DCI, NH₃): m/z=426 (M+NH₄ ⁺).

Example XLVII 4-(Biphenyl-4-ylmethoxy)phenyl acetate

2.35 g of anhydrous potassium carbonate are added to a solution of 2.80g of 4-biphenylmethyl bromide and 1.72 g of 4-hydroxyphenyl acetate in75 ml of butyronitrile, and the reaction mixture is stirred at 120° C.overnight. It is filtered with suction, washed with acetonitrile, andconcentrated. The residue is taken up in ethyl acetate, washed withwater and saturated sodium chloride solution, dried over sodium sulphateand filtered, and the solvent is removed in a rotary evaporator. This isfollowed by stirring with ethyl acetate, filtration with suction andwashing of the resulting crystals several times with ethyl acetate. 1.36g of product are obtained. A further 0.36 g of product can be isolatedfrom the mother liquor after concentration and chromatography on silicagel with dichloromethane.

HPLC (method 5): R_(t): 5.04 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 7.73-7.62 (m, 4H), 7.58-7.32 (m, 5H),7.05 (s, 4H), 5.15 (s, 2H), 2.24 (s, 3H).

MS (EI): m/z=318 (M⁺).

Example XLVIII 4-(Biphenyl-4-ylmethoxy)phenol

1.30 g of 4-(biphenyl-4-ylmethoxy)phenyl acetate in 25 ml of THF areslowly added dropwise to 4.5 ml of a solution of lithium aluminiumhydride (1 molar in THF). The reaction is complete after 30 minutes, andhydrochloric acid (1 molar) is added dropwise until the precipitatewhich has initially separated out redissolves. The solution is extractedwith dichloromethane, the organic phase is washed once each with waterand saturated sodium chloride solution, dried over sodium sulphate andfiltered, and the solvent is removed in a rotary evaporator. 1.11 g ofproduct are obtained.

HPLC (method 5): R_(t): 4.75 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 8.89 (s, 1H), 7.66 (d, 4H), 7.53-7.33(m, 5H), 6.84 (d, 2H), 6.68 (d, 2H), 5.04 (s, 2H).

MS (DCI, NH₃): m/z=294 (M+NH₄ ⁺).

Example XLIX Methyl [4-(biphenyl-4-ylmethoxy)phenoxy]acetate

1.95 g of caesium carbonate are added to a solution of 1.10 g of4-(biphenyl-4-ylmethoxy)phenol and 0.41 ml of methyl bromoacetate in 20ml of DMF, and the reaction mixture is stirred at room temperatureovernight and then at 80° C. for 4 hours. The solvent is removed in arotary evaporator, the residue is triturated with water, and thecrystals which have separated out are filtered off with suction anddried at 40° C. under high vacuum overnight. 1.36 g of product areobtained.

HPLC (method 5): R_(t): 4.98 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 7.66-7.41 (m, 9H), 6.98-6.81 (m, 4H),5.05 (s, 2H), 4.58 (s, 2H), 3.81 (s, 3H).

MS (DCI, NH₃): m/z=366 (M+NH₄ ⁺).

Example L 2-[4-(Biphenyl-4-ylmethoxy)phenoxy]ethanol

3.82 ml of lithium aluminium hydride (1 molar in THF) are slowly addeddropwise to a solution of 1.21 g of methyl[4-(biphenyl-4-ylmethoxy)phenoxy]acetate in 40 ml of THF. The mixture isstirred at room temperature overnight. After addition of hydrochloricacid (1 molar), dichloromethane and water, the insoluble crystals arefiltered off with suction and dried at 40° C. under high vacuumovernight (221 mg of product). A further 700 mg of product are obtainedfrom the organic phase after washing with water and saturated sodiumchloride solution, drying over sodium sulphate, filtration and removalof the solvent in vacuo.

HPLC (method 5): R_(t): 4.73 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 7.77-7.32 (m, 9H), 6.98-6.80 (m, 4H),5.07 (s, 2H), 4.84 (t, 1H), 3.92 (s, 2H), 3.77-3.60 (m, 2H).

MS (DCI, NH₃): m/z=338 (M+NH₄ ⁺).

Example LI 4-{[4-(2-Bromoethoxy)phenoxy]methyl}biphenyl

800 mg of 2-[4-(biphenyl-4-ylmethoxy)phenoxy]ethanol are introduced into25 ml of dichloromethane under argon, 1.16 g of tetrabromomethane areadded, and the mixture is stirred at room temperture for 10 minutes. Themixture is cooled to 0° C. and, after addition of 1.83 g oftriphenylphosphine, stirred at 0° C. for one hour and at roomtemperature for 2 hours. It is concentrated, and the residue is taken upin a little dichloromethane and filtered through silica gel. 480 mg ofproduct are obtained.

HPLC (method 5): R_(t): 5.30 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.73-7.63 (m, 4H), 7.56-7.33 (m, 5H),7.02-6.88 (m, 4H), 5.11 (s, 2H), 4.26 (t, 2H), 3.77 (t, 2H).

MS (EI): m/z=383 and 385 (M⁺).

Example LII Methyl {4-[5-phenoxypent-1-en-1-yl]phenoxy}acetate (E/Zmixture)

Preparation takes place in analogy to Example XLIII from methyl(4-formylphenoxy)acetate and (4-phenoxybutyl)(triphenyl)phosphoniumbromide. The product is obtained as an E/Z mixture.

HPLC (method 5): R_(t): 5.03 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.32-7.18 (m, 4H), 6.96-6.81 (m, 5H),6.43-6.34 (m, 1H), 6.12 (dt, 0.5H), 5.63 (dt, 0.5H), 4.62 (d, 2H), 4.00(q, 2H), 3.81 (d, 3H), 2.50 (dq, 1H), 2.38 (dq, 1H), 2.01-1.87 (m, 2H).

LC-MS (method 10): R_(t): 3.49 min, m/z=233 (M−C₆H₅O).

Example LIII 2-{4-[(1 Z)-5-Phenoxypent-1-en-1-yl]phenoxy}ethanol

Preparation takes place in analogy to Example XLIV from methyl{4-[5-phenoxypent-1-en-1-yl]phenoxy}acetate (E/Z mixture). Thedouble-bond isomers are separated by HPLC (stability. C-30 5 μm 250mm×20 mm No. 20101; acetonitrile/water 3:1; flow rate: 25 ml/min; UVdetection: 210 nm).

HPLC (method 5): R_(t): 4.80 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.30-7.20 (m, 4H), 6.93 (t, 1H),6.60-6.85 (m, 4H), 6.39 (d, 1H), 5.62 (dt, 1H), 4.11-4.07 (m, 2H),4.01-3.95 (m, 4H), 2.51 (dq, 2H), 2.00-1.91 (m, 3H).

LC-MS (method 9): R_(t): 2.51 min, m/z=205 (M−C₆H₅O).

Example LIV 1-(2-Iodoethoxy)-4-[(1Z)-5-phenoxypent-1-en-1-yl]benzene

Preparation takes place in analogy to Example XLVI from2-{4-[(1Z)-5-phenoxypent-1-en-1-yl]phenoxy}ethanol.

HPLC (method 5): R_(t): 5.55 min.

Example LV 1-Iodo-4-(4-phenoxybutoxy)benzene

Preparation takes place in analogy to Example XVII from 4-phenoxybutylbromide and 4-iodophenol.

HPLC (method 5): R_(t): 5.56 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 7.60-7.49 (m, 2H), 7.37-7.20 (m, 2H),7.00-6.82 (m, 3H), 6.74-6.62 (m, 2H), 4.10-3.90 (m, 4H), 2.06-1.89 (m,4H).

MS (DCI, NH₃): m/z=386 (M+NH₄ ⁺).

Example LVI 3-[4-(4-phenoxybutoxy)phenyl]prop-2-yn-1-ol

155 mg of copper(I) iodide, 57 mg of triphenylphosphine and 152 mg ofbis(triphenylphosphine)palladium(II) chloride are added to a solution of1.00 g of 1-iodo-4-(4-phenoxybutoxy)benzene in 15 ml triethylamine underargon. 457 mg of propargyl alcohol are added dropwise to the mixture,and it is stirred at 60° C. for one hour. The reaction mixture isfiltered through Celite and washed several times with ethyl acetate anddichloromethane. The combined phases are washed three times with water,twice with dilute hydrochloric acid and once with saturated sodiumchloride solution, dried over sodium sulphate, filtered andconcentrated. The residue is purified on silica gel withcyclohexane/ethyl acetate 5:1. 737 mg of product are obtained.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.40-7.23 (m, 4H), 6.96-6.79 (m, 5H),4.48 (d, 2H), 4.08-3.98 (m, 4H), 2.03-1.94 (m, 4H), 1.57 (t, 1H).

MS (DCI, NH₃): m/z=297 (M+NH₄ ⁺).

Example LVII 1-(3-Bromoprop-1-yn-1-yl)-4-(4-phenoxybutoxy)benzene

Preparation takes place in analogy to Example IV from3-[4-(4-phenoxybutoxy)phenyl]prop-2-yn-1-ol.

HPLC (method 5): R_(t): 5.32 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.40-7.23 (m, 4H), 6.97-6.79 (m, 5H),4.16 (s, 2H), 4.10-3.96 (m, 4H), 2.03-1.92 (m, 4H).

MS (DCI, NH₃): m/z=376 and 378 (M+NH₄ ⁺).

Example LVIII 2-[4-(5-phenoxypentyl)phenoxy]ethanol

Preparation takes place in analogy to Example XLV from2-{4-[5-phenoxypent-1-en-1-yl]phenoxy}ethanol.

HPLC (method 5): R_(t): 4.88 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.30-7.23 (m, 2H), 7.12-7.07 (m, 2H),6.95-6.82 (m, 5H), 4.09-4.05 (m, 2H), 3.98-3.91 (m, 4H), 2.59 (t, 2H),1.99 (t, 1H), 1.85-1.75 (m, 2H), 1.72-1.61 (m, 2H), 1.55-1.43 (m, 2H).

LC-MS (method 10): R_(t): 3.35 min, m/z (EI+)=300.

Example LIX 1-(2-Iodoethoxy)-4-(5-phenoxypentyl)benzene

Preparation takes place in analogy to Example XLVI from2-[4-(5-phenoxypentyl)-phenoxy]ethanol.

HPLC (method 5): R_(t): 5.58 min.

MS (DCI, NH₃): m/z=428 (M+NH₄ ⁺).

Example LX Methyl 3-{4-[(4-phenoxybut-2-yn-1-yl)oxy]phenyl}propanoate

Preparation takes place in analogy to Example XVII from[(4-bromobut-2-yn-1-yl)oxy]benzene and methyl3-(4-hydroxyphenyl)propanoate.

HPLC (method 5): R_(t): 4.77 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.27 (dd, 2H), 7.09 (d 2H), 7.03-6.90(m, 3H), 6.86 (d, 2H), 4.70 (dd, 4H), 3.67 (s, 3H), 2.89 (t, 2H), 2.59(t, 2H).

MS (DCI, NH₃): m/z=342 (M+NH₄ ⁺).

Example LXI 3-{4-[(4-phenoxybut-2-yn-1-yl)oxy]phenyl}propan-1-ol

Preparation takes place in analogy to Example II from methyl3-{4-[(4-phenoxybut-2-yn-1-yl)oxy]phenyl}propanoate.

HPLC (method 5): R_(t): 4.42 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.31-7.24 (m, 2H), 7.10 (d, 2H), 7.00(d, 1H), 6.94 (dd, 2H), 6.86 (d, 2H), 4.71 (dd, 4H), 3.71-3.62 (m, 2H),2.66 (t, 2H), 1.92-1.82 (m, 2H), 1.22 (t, 1H).

MS (DCI, NH₃): m/z=314 (M+NH₄ ⁺).

Example LXII 1-(3-Bromopropyl)-4-[(4-phenoxybut-2-yn-1-yl)oxy]benzene

Preparation takes place in analogy to Example IV from3-{4-[(4-phenoxybut-2-yn-1-yl)oxy]phenyl}propan-1-ol.

HPLC (method 5): R_(t): 5.17 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.32-7.24 (m, 2H), 7.09 (d, 2H), 7.00(d, 1H), 6.94 (dd, 2H), 6.87 (d, 2H), 4.71 (dd, 4H), 3.38 (t, 2H), 2.72(t, 2H), 2.13 (quint, 2H).

LC-MS (method 9): R_(t): 2.88 min, m/z (EI+)=358 and 360.

Example LXIII Ethyl 3-{4-[5-phenoxypent-1-en-1-yl]phenyl}propanoate (E/Zmixture)

Preparation takes place in analogy to Example XLIII from(4-phenoxybutyl)-(triphenyl)phosphonium bromide and ethyl3-(4-formylphenyl)propanoate. The product is obtained as an E/Z mixture.

HPLC (method 5): R_(t): 5.38 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.31-7.10 (m, 6H), 6.96-6.83 (m, 3H),6.46-6.36 (m, 1H), 6.20 (dt, 0.37H), 5.66 (dt, 0.63H), 4.12 (dq, 2H),3.99 (q, 2H), 2.98-2.88 (m, 2H), 2.64-2.56 (m, 2H), 2.51 (dq, 1.25H),2.39 (q, 0.75H), 2.00-1.88 (m, 2H), 1.23 (t, 3H).

LC-MS (method 9): R_(t): 3.01 min, m/z (EI+)=338.

Example LXIV 3-{4-[(1Z)-5-phenoxypent-1-en-1-yl]phenyl}propan-1-ol

Preparation takes place in analogy to Example XLIV from ethyl3-{4-[5-phenoxypent-1-en-1-yl]phenyl}propanoate (E/Z mixture). Thedouble-bond isomers are separated by HPLC (Kromasil 100 C-18 5 μm 250mm×20 mm; methanol/water 3:1; flow rate: 25 ml/min; UV detection: 210nm).

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.30-7.24 (m, 2H), 7.22 (d, 2H), 7.15(d, 2H), 6.93 (t, 1H), 6.87 (d, 2H), 6.43 (d, 1H), 5.66 (dt, 1H), 3.98(t, 2H), 3.68 (t, 2H), 2.70 (t, 2H), 2.53 (dq, 2H), 1.98-1.86 (m, 4H),1.23 (s, broad, 1H).

LC-MS (method 9): R_(t): 2.61 min, m/z=203 (M−OC₆H₅).

Example LXV (4Z)-5-[4-(3-Bromopropyl)phenyl]pent-4-en-1-yl phenyl ether

Preparation takes place in analogy to Example IV from3-{4[(1Z)-5-phenoxypent-1-en-1-yl]phenyl}propan-1-ol.

HPLC (method 5): R_(t): 5.69 min.

Example LXVI 3-{4-[(1E)-5-Phenoxypent-1-en-1-yl]phenyl}propan-1-ol

Preparation takes place in analogy to Example XLIV from ethyl3-{4-[5-phenoxypent-1-en-1-yl]phenyl}propanoate (E/Z mixture). Thedouble-bond isomers are separated by HPLC (Kromasil 100 C-18 5 μm 250mm×20 mm; methanol/water 3:1; flow rate: 25 ml/min; UV detection: 210nm].

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 7.30-7.24 (m, 4H), 7.13 (d, 2H),6.96-6.88 (m, 3H), 6.41 (d, 1H), 6.21 (dt, 1H), 4.01 (t, 2H), 3.68 (t,2H), 2.69 (t, 2H), 2.39 (q, 2H), 2.00-1.84 (m, 4H), 1.23 (s, broad, 1H).

LC-MS (method 9): R_(t): 2.63 min, m/z=203 (M−OC₆H₅).

Example LXVII (4E)-5-[4-(3-Bromopropyl)phenyl]pent-4-en-1-yl phenylether

Preparation takes place in analogy to Example IV from3-{4-[(1E)-5-phenoxypent-1-en-1-yl]phenyl}propan-1-ol.

HPLC (method 5): R_(t): 5.68 min.

Example LXVIII Methyl (2E)-3-[4-(4-phenoxybutoxy)phenyl]acrylate

Preparation takes place in analogy to Example I from methyl(2E)-3-(4-hydroxy-phenyl)acrylate and (4-bromobutoxy)benzene.

HPLC (method 2): R_(t): 5.4 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 7.73-7.61 (m, 3H), 7.34-7.22 (m, 2H),7.04-6.86 (m, 5H), 6.48 (d, 1H), 4.15-3.95 (m, 4H); 3.70 (s, 3H),1.93.1.81 (m, 4H).

MS (DCI, NH₃): m/z=327 (M+H⁺), 344 (M+NH₄ ⁺).

Example LXIX (2E)-3-[4-(4-Phenoxybutoxy)phenyl]prop-2-en-1-ol

Preparation takes place in analogy to Example II from methyl(2E)-3-[4-(4-phenoxybutoxy)phenyl]acrylate.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.34-7.24 (m, 4H), 6.97-6.82 (m, 5H),6.56 (d, 1H), 6.23 (dt, 1H), 4.30 (d,2H), 4.07-4.01 (m, 4H), 2.01-1.95(m, 4H), 1.36 (s, broad, 1H).

Example LXX 1-[(1E)-3-Bromoprop-1-en-1-yl]-4-(4-phenoxybutoxy)benzene

A solution of 250 mg of (2E)-3-[4-(4-phenoxybutoxy)phenyl]prop-2-en-1-olin 10 ml of dichloromethane is cooled to −10° C., and 82 mg ofphosphorus tribromide in 0.5 ml of dichloromethane are added dropwise.The mixture is stirred for one hour, during which it warms to roomtemperature. Saturated sodium bicarbonate solution is added to themixture, which is extracted several times with diethyl ether, and theorganic phase is dried over sodium sulphate, filtered and concentrated.164 mg of product are obtained.

HPLC (method 5): R_(t): 5.20 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.35-7.21 (m, 4H), 6.98-6.80 (m, 5H),6.58 (d, 1H), 6.25 (dt, 1H), 4.17 (d,2H), 4.08-3.96 (m, 4H), 2.06-1.92(m, 4H).

MS (DCI, NH₃): m/z=378 and 380 (M+NH₄ ⁺), 281 (M−Br⁻).

Example LXXI [2-(Methoxycarbonyl)cyclohexyl]-methaneammonium bromide

2.90 g of octahydro-1H-isoindol-1-one are stirred in 80 ml ofconcentrated hydrobromic acid at 100° C. overnight. Addition of about 5ml of methanol is followed by heating for a further 5 hours and, aftercooling, the reaction mixture is concentrated. Seed crystals are addedto the residue, or it is scratched, it is then stirred with ethylacetate and filtered with suction to remove solvent. For completeconversion, it is taken up in about 5 ml of methanol and, after additionof a few drops of concentrated sulphuric acid, stirred under reflux forabout two hours. After cooling, the reaction mixture is concentrated,stirred with ethyl acetate, filtered with suction and dried in vacuo.

HPLC (method 5): R_(t): 3.15 min.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.75 (s, broad, 3H), 3.61 (s, 3H),2.95-2.73 (m, 3H), 2.05-1.92 (m, 1H), 1.86-1.73 (m, 1H), 1.66-1.22 (7H).

MS (DCI, NH₃): m/z=172 (M+H⁺).

Example LXXII Methyl1-[5-(methoxycarbonyl)-2-(3-{4-[(triisopropylsilyl)oxy]phenyl}propoxy)-benzoyl]piperidine-4-carboxylate

Methyl1-[5-(methoxycarbonyl)-2-(3-{4-[(triisopropylsilyl)oxy]phenyl}propoxy)-benzoyl]piperidine-4-carboxylateis prepared by the process described in Example XLI from[4-(3-bromopropyl)phenoxy](triisopropyl)silane and methyl1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate.

HPLC (method 4): R_(t): 6.63 min.

MS (ESI): m/z 612 (M+H⁺).

Example LXXIII Methyl1-[2-[3-(4-hydroxyphenyl)propoxy]-5-(methoxycarbonyl)benzoyl]piperidine-4-carboxylate

Methyl1-[2-[3-(4-hydroxyphenyl)propoxy]-5-(methoxycarbonyl)benzoyl]piperidine-4-carboxylateis prepared in analogy to the process described in Example XLII frommethyl1-[5-(methoxycarbonyl)-2-(3-{4-[(triisopropylsilyl)oxy]phenyl}propoxy)-benzoyl]piperidine-4-carboxylate.

HPLC (method 1): R_(t): 4.30 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 8.02 (dd, 1H), 7.93 and 7.90 (2 d,together 1H), 7.00 (d, 2H), 6.88 (d, 1H), 6.75 (d, 2H), 5.67 (d, 1H),4.62 (m, 1H), 4.02 (m, 2H), 3.87 (s, 3H), 3.70 and 3.63 (2 s, together3H), 3.49 (m, 1H), 3.27 (m, 1H), 3.12-2.95 (m, 2H), 2.72-2.52 (m, 3H),2.11-1.97 (m, 3H), 1.84-1.63 (m, 2H).

MS (DCI, NH₃): m/z=456 (M+H⁺).

Exemplary Embodiments Example 1 Methyl1-[5-(methoxycarbonyl)-2-({3-[4-(4-phenoxybutoxy)phenyl]propanoyl}-amino)benzoyl]-4-piperidinecarboxylate

2 ml of pyridine and a solution of 470 mg of3-[4-(4-phenoxybutoxy)phenyl]propanoyl chloride in 7.5 ml ofdichloromethane are added to a solution of 450 mg of methyl1-[2-amino-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate in 7.5 mlof dichloromethane. The reaction mixture is left to stir at roomtemperature for 15 hours. It is then acidified with 2 molar hydrochloricacid and extracted with ethyl acetate. The organic extract is washedwith saturated brine and dried over anhydrous sodium sulphate.Filtration and evaporation result in a crude product which is purifiedby flash chromatography (silica gel, cyclohexane/ethyl acetate 2:1). 617mg of product are obtained.

TLC: R_(f): 0.55 (cyclohexane/ethyl acetate 1:9).

HPLC (method 1): R_(t): 5.08 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 9.76 (s, 1H), 7.97 (dd, 1H), 7.82-7.77(m, 2H), 7.30-7.23 (m, 2H), 7.13 (d, 2H), 6.93-6.89 (m, 3H), 6.84 (d,2H), 4.32 (m 1H), 4.00 (m, 4H), 3.83 (s, 3H), 3.60 (s, 3H), 2.92-2.77(m, 4H), 2.64-2.56 (m, 3H), 1.93-1.42 (m, 9H).

MS (ESI+): m/z 617 (M+H⁺).

Example 2 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate(racemate B)

A solution von 542 mg of 1-(3-bromopropyl)-4-(4-phenoxybutoxy)benzeneand 500 mg of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-benzoate(racemate B) in 50 ml of butyronitrile is mixed with 248 mg of potassiumcarbonate and heated to reflux for 15 hours. 5% strength sodiumdihydrogen phosphate solution is then added to the reaction mixture, andit is extracted with ethyl acetate. The organic extract is washed withsaturated brine and dried over anhydrous sodium sulphate. Filtration andevaporation result in a crude product which is purified by suctionfiltration through silica gel with cyclohexane/ethyl acetate 2:1 asmobile phase. 672 mg of product are obtained.

TLC: R_(f): 0.33 (cyclohexane/ethyl acetate 1:1).

HPLC (method 1): R_(t): 5.68 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.21 (d, 1M, 8.08 (d broad, 1H), 8.00(dd, 1H), 7.30-7.20 (m, 3H), 7.12 (d, 2H), 6.94-6.88 (m, 3H), 6.84 (d,2H), 4.17-4.12 (m, 3H), 4.01 (m, 4H), 3.83 (s, 3H), 3.57 (s, 3H),2.73-2.68 (m, 3H), 2.08 (m, 1H), 1.88-1.81 (m, 6H), 1.69-1.49 (m, 6H).

MS (ESI+): m/z=618 (M+H⁺), 640 (M+Na⁺).

Example 3 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxy-butoxy)phenyl]propoxy}benzoate(racemate A)

Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxy-butoxy)phenyl]propoxy}benzoate(racemate A) is prepared in analogy to the process described in Example2 from 1-(3-bromopropyl)-4-(4-phenoxybutoxy)benzene and methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(racemate A).

TLC: R_(f): 0.38 (cyclohexane/ethyl acetate 1:1).

HPLC (method 1): R_(t): 5.67 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.20 (d, 1H), 8.07 (d broad, 1H), 8.00(dd, 1H), 7.30-7.18 (m, 3H), 7.12 (d, 2H), 6.94-6.88 (m, 3H), 6.84 (d,2H), 4.13 (t, 2H), 4.01 (m, 4H), 3.84 (m, 1H), 3.83 (s, 3H), 3.57 (s,3H), 2.70 (t, 2H), 2.48 (m, 1H), 2.17 (m, 1H), 2.03 (m, 2H), 1.92-1.73(m, 7H), 1.43-1.12 (m, 4H).

MS (ESI): m/z=618 (M+H⁺), 640 (M+Na⁺).

Example 4 Methyl1-(5-(methoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}-benzoyl)-4-piperidinecarboxylate

Methyl1-(5-(methoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}-benzoyl)-4-piperidinecarboxylateis prepared in analogy to the process described in Example 2 from1-(3-bromopropyl)-4-(4-phenoxybutoxy)benzene and methyl1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate.

HPLC (method 1): R_(t): 5.42 min.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.97 (d, 1H), 7.73 (dd, 1H), 7.29-7.25(m, 2H), 7.17 (d, 1H), 7.12-7.09 (m, 2H), 6.93-6.90 (m, 3H), 6.86-6.83(m, 2H), 4.43 (m, 1H), 4.16-3.97 (m, 6H), 3.82 (s, 3H), 3.60 and 3.54 (2s, 3H), 3.29 (m, 1H), 3.11-2.98 (m, 1H), 2.92 (m, 1H), 2.71-2.60 (m,3H), 2.03-1.72 (m, 8), 1.64-1.50 (m, 2H).

MS (DCI, NH₃+): m/z=604.3 (M+H⁺), 621.3 (M+NH₄ ⁺).

Example 5 Methyl1-[2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)-benzoyl]-4-piperidinecarboxylate

75 mg of N-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride(EDC), 27 mg of 1-hydroxy-1H-benzotriazole hydrate (HOBT) and 40 mg oftriethylamine, are successively added to a suspension of 100 mg of2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoicacid and 39 mg of methyl piperidine-4-carboxylate hydrochloride in 30 mlof dichloromethane. Water is added to the reaction mixture after 15hours at room temperature. After phase separation, the aqueous phase isextracted with ethyl acetate. The combined dichloromethane and ethylacetate phases are washed with saturated brine and dried over anhydroussodium sulphate. Filtration and concentration result in a crude productwhich is purified by suction filtration through silica gel withcyclohexane/ethyl acetate 1:1 as mobile phase. 120 mg of product areobtained.

HPLC (method 1): R_(t): 5.75 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 7.97 (dd, 1H), 7.75-7.66 (m, 5H),7.53-7.37 (m, 5H), 7.19-7.11 (m, 3H); 6.96-6.92 (m, 2H), 5.12 (s, 2H),4.48-4.37 (m, 1H), 4.28 (quart; 2H), 4.13-3.98 (m, 2H), 3.60 and 3.53 (2s, 3H), 3.28 (m, 1H), 3.14-2.86 (m, 2H), 2.71-2.59 (m, 3H), 2.02-1.88(m, 3H), 1.79-1.54 (m, 3H), 1.31 (t, 3H).

MS (ESI+): m/z=636.1 (M+H⁺).

Example 6 Ethyl3-({cis-[2-(ethoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxy-butoxy)phenyl]propoxy}benzoate

39 mg (0.20 mmol) of N-[(3-dimethylamino)propyl]-N′-ethylcarbodiimidehydrochloride (EDC) and 27.4 mg (0.20 mmol) of1-hydroxy-1H-benzotriazole hydrate (HOBT) are successively added to asuspension of 100 mg (0.20 mmol) of5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoic acidin 30 ml of dichloromethane at RT. After 30 min, 41 mg (0.41 mmol) oftriethylamine and 38 mg (0.18 mmol) of ethylcis-2-amino-1-cyclohexanecarboxylate hydrochloride are added, and themixture is stirred overnight. 10 ml of water are then added, the phasesare separated, and the aqueous phase is extracted with dichloromethane(three times 25 ml). The combined organic phases are washed withsaturated sodium chloride solution, dried, (sodium sulphate) andconcentrated in a rotary evaporator. The crude product is purified bycolumn chromatography (silica gel 60, mobile phase gradientcyclohexane-->cyclohexane-ethyl acetate 5:1). 102 mg of product areobtained.

HPLC (method 2): R_(t): 6.22 min

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.33 (d, 1H), 8.43 (d, 1H), 8.07 (dd,1H), 7.31-7.23 (m, 2H), 7.11 (d, 2H), 6.96-6.86 (m, 4H), 6.83 (d, 2H),4.47 (m, 1H), 4.35 (m, 2H), 4.23-3.96 (m, 8H); 2.93-2.70 (m, 3H),2.38-2.15 (m, 2H), 2.12-1.90 (m, 6H), 1.81-1.61 (m, 3H), 1.37 (t, 3H),1.19 (t, 3H).

MS (ESIpos): m/z=646 (M+H)⁺

Example 7 Ethyl3-{[4-(2-ethoxy-2-oxoethyl)-1-piperidinyl]carbonyl}-4-{3-[(4-phenoxybutoxy)phenyl]propoxy}benzoate

The compound is prepared in analogy to the process described in Example6 from5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)-phenyl]propoxy}benzoic acidand ethyl 4-piperidineacetate [CAS No. 59184-90-6]. The crude product ispurified by HPLC [YMC GEL ODS-AQ-S 5/15 μm, gradient:acetonitrile/(water+0.2% TFA) 10:90 . . . 95:5].

LC-MS (method 3): R_(t): 5.12 min.

MS (ESI+): m/z=646 (M+H⁺).

Example 8 Methyl1-(5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoyl)-3-azetidinecarboxylate

The compound is prepared in analogy to the process described in Example6 from5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoic acidand methyl 3-azetidinecarboxylate [CAS No. 343238-58-4]. The crudeproduct is immediately reacted further without purification.

LC-MS (method 3): R_(t): 4.84 min.

MS (ESI+): m/z=590 (M+H⁺).

Example 9 Ethyl4-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({cis-[2-(ethoxy-carbonyl)cyclohexyl]amino}carbonyl)benzoate

The compound is prepared in analogy to the process described in Example6 from2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoicacid and ethyl cis-2-amino-1-cyclohexanecarboxylate hydrochloride.

HPLC (method 4): R_(t): 6.42 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 8.43-8.33 (m, 2H), 8.03 (dd, 1H),7.71-7.63 (m, 4H), 7.56-7.11 (m, 8H), 6.95 (d, 2H), 5.12 (s, 2H),4.48-4.14 (m, 5H), 3.99 (m, 2H), 2.86-2.65 (m, 3H), 2.22-2.03 (m, 2H),1.92-1.24 (m, 8H), 1.31 (t, 3H), 1.08 (t, 3H).

MS (ESI+): m/z=664 (M+H⁺).

Example 10 Ethyl4-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({cis-[4-(methoxy-carbonyl)cyclohexyl]amino}carbonyl)benzoate

The compound is prepared in analogy to the process described in Example6 from2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoicacid and ethyl cis-4-amino-1-cyclohexanecarboxylate.

HPLC (method 2): R_(t): 5.93 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.21 (d, 1H), 8.08 (d, 1H), 7.99 (dd,1H), 7.70-7.64 (m, 4H), 7.54-7.43 (m, 4H), 7.40-7.33 (m, 1H), 7.20 (d,1H), 7.14 (d, 2H), 6.94 (d, 2H), 5.11 (s, 2H), 4.30 (q, 2H), 4.14 (t,2H), 3.97 (m, broad, 1H), 3.53 (s, 3H), 2.69 (t, 2H), 2.50 (m,concealed, 1H), 2.06 (m, 2H), 2.90-1.76 (m, 2H), 1.75-1.54 (m, 6H), 1.31(t, 3H).

MS (ESI+): m/z=650 (M+H⁺).

Example 113-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid (racemate B)

A solution of 638 mg of methyl3-({[3-(methoxycarbonyl)cyclohexyl]-amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate(racemate B) in 4 ml of tetrahydrofuran (THF) and 4 ml of methanol ismixed with 4 ml of 2 molar sodium hydroxide solution and heated at 60°C. for one hour. The pH is then adjusted to a value of 3-4 with 2 molarhydrochloric acid, and the mixture is extracted with ethyl acetate. Theorganic extract is washed with saturated sodium chloride solution anddried over anhydrous sodium sulphate. Filtration and evaporation resultin a crude product which is purified by recrystallization from diethylether. 589 mg of product are isolated.

Melting point: 182-183° C.

HPLC (method 1): R_(t): 4.95 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.38 (s broad, 2H), 8.21 (d, 1H),8.05 (d, 1H), 7.98 (dd, 1H), 7.29-7.23 (m, 2H), 7.19-7.11 (m, 3H),6.93-6.88 (m, 3H), 6.85 (d, 2H), 4.15-4.10 (m, 3H), 4.01 (m, 4H), 2.71(t, 2H), 2.62 (m, 1H), 2.07 (m, 2H), 1.91-1.70 (m, 6H), 1.62-1.16 (m,6H).

MS (ESI+): m/z=590 (M+H⁺), 612 (M+Na⁺).

Example 123-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid (racemate A)

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid (racemate A) is prepared in analogy to the process described inExample 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate(racemate A).

Melting point: >210° C.

HPLC (method 1): R_(t): 4.91 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.48 (s broad, 2H), 8.18 (d, 1H),8.09 (d, 1H), 7.98 (dd, 1H), 7.32-7.11 (m, 5H), 6.96-6.83 (m, 5H), 4.12(t, 2H), 4.01 (m, 4H), 3.82 (m, 1H), 2.70 (t, 2H), 2.38 (m, 1H),2.19-1.73 (m, 10H), 1.41-1.10 (m, 4H).

MS (ESI+): m/z=590 (M+H⁺), 612 (M+Na⁺).

Example 131-(2-{3-[4-(1,1′-Biphenyl-4-ylmethoxy)phenyl]propoxy}-5-carboxybenzoyl)-4-piperidinecarboxylicacid

1-(2-{3-[4-(1,1′-Biphenyl-4-ylmethoxy)phenyl]propoxy}-5-carboxybenzoyl)-4-piperidinecarboxylicacid is prepared in analogy to the process described in Example 11 frommethyl1-[2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)-benzoyl]-4-piperidinecarboxylate.

Melting point: 193-194° C.

HPLC (method 1): R_(t): 4.93 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.31 (s broad, 2H), 7.93 (dd, 1H),7.72-7.64 (m, 5H), 7.55-7.32 (m, 5H), 7.17-7.12 (m, 3H), 6.98-6.92 (m,2H), 5.12 (s, 2H), 4.48-4.37 (m, 1H), 4.15-3.97 (m, 2H), 3.29 (m, 1H),3.13-2.83 (m, 2H), 2.70-2.59 (m, 3H), 2.02-1.89 (m, 3H), 1.80-1.70 (m,1H), 1.62-1.47 (m, 2H).

MS (ESI+): 594 (M+H⁺), 616 (M+Na⁺).

Example 141-[5-Carboxy-2-({3-[4-(4-phenoxybutoxy)phenyl]propanoyl}amino)benzoyl]-4-piperidinecarboxylicacid

1-[5-Carboxy-2-({3-[4-(4-phenoxybutoxy)phenyl]propanoyl}amino)benzoyl]-4-piperidinecarboxylicacid is prepared in analogy to the process described in Example 11 frommethyl1-[5-(methoxycarbonyl)-2-({3-[4-(4-phenoxybutoxy)phenyl]-propanoyl}amino)benzoyl]-4-piperidinecarboxylate.

HPLC (method 1): R_(t): 4.61 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.63 (s broad, 2H), 9.73 (s, 1H),7.93 (dd, 1H), 7.77-7.73 (m, 2H), 7.29-7.25 (m, 2H), 7.14 (d, 2H),6.93-6.90 (m, 3H), 6.84 (d, 2H), 4.32 (m 1H), 4.00 (m, 4H), 3.30 (1H),2.90-2.78 (m, 4H), 2.62 (m, 2H), 2.48 (m, 1H), 1.93-1.82 (m, 5H), 1.69(m, 1H), 1.59-1.39 (m, 2H).

MS (ESI−): m/z=587.2 (M−H⁻).

Example 151-(5-Carboxy-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoyl)-4-piperidine-carboxylicacid

1-(5-Carboxy-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoyl)-4-piperidine-carboxylicacid is prepared in analogy to the process described in Example 11 frommethyl1-(5-(methoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}-benzoyl)-4-piperidinecarboxylate.

Melting point: 142-143° C.

HPLC (method 1): R_(t): 4.70 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.93 (dd, 1H), 7.70 (dd, 1H),7.29-7.24 (m, 2H), 7.17-7.11 (m, 3H), 6.93-6.82 (m, 5H), 4.41 (m, 1H),4.13-3.96 (m, 6H), 3.31 (m, 1H), 3.11-2.89 (m, 2H), 2.63 (t, 2H), 2.53(m, 1H), 1.99-1.83 (m, 7), 1.76 (m, 1H), 1.67-1.48 (m, 2H).

MS (DCI, NH₃ ⁺): m/z 576.3 (M+H⁺), 593.2 (M+NH₄ ⁺).

Example 163-{[(4-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid

3-{[(4-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid is prepared in analogy to the process described in Example 11 frommethyl3-({[4-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate.

Melting point: 163-165° C.

¹H NMR (500 MHz, DMSO-d₆, δ/ppm): 8.21 (d, 1H), 8.09 (d, 1H), 7.97 (dd,2H), 7.30-7.22 (m, 2H), 7.16 (d, 1H), 7.11 (d, 2H), 6.99-6.82 (m, 5H),4.12 (t, 2H), 4.02-3.95 (m, 5H), 2.68 (t, 2H), 2.28 (t, 1H), 2.10-2.00(m, 2H), 1.90-1.76 (m, 6H), 1.72-1.60 (m, 6H).

MS: m/z=590 (M+H⁺).

Example 174-{3-[4-(1,1′-Biphenyl-4-ylmethoxy)phenyl]propoxy}-3-{[cis-(4-carboxycyclohexyl)amino]carbonyl}benzoicacid

The compound is prepared in analogy to the process described in Example11 from ethyl4-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({cis-[4-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate.

HPLC (method 2): R_(t): 5.04 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.41 (s, broad, 2H), 8.21 (d, 1H),8.09 (d, 1H), 7.96 (dd, 1H), 7.70-7.63 (m, 4H), 7.54-7.43 (m, 4H),7.40-7.33 (m, 1H), 7.18-7.12 (m, 3H), 6.95 (d, 2H), 5.11 (s, 2H), 4.12(t, 2H), 3.97 (m, broad, 1H), 2.69 (t, 2H), 2.41 (m, broad, 1H), 2.08(m, 2H), 1.90-1.78 (m, 2H), 1.75-1.55 (m, 6H).

MS (ESI+): m/z=608 (M+H⁺).

Example 183-{[4-(Carboxymethyl)-1-piperidinyl]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid

The compound is prepared in analogy to the process described in Example11 from ethyl3-{[4-(2-ethoxy-2-oxoethyl)-1-piperidinyl]carbonyl}-4-{3-[(4-phenoxybutoxy)-phenyl]propoxy}benzoate.The crude product obtained is purified by HPLC [YMC GEL ODS-AQ-S 5/15μm, gradient: acetonitrile/(water+0.2% TFA) 10:90 . . . 95:5].

Melting point: 192° C.

LC-MS (method 3): R_(t): 3.76 min.

¹H-NMR (300 MHz, DMSO-d_(6 δ)/ppm): 12.40 (s, broad, 2H), 7.94-7.91 (m,1), 7.68 (dd, 1H), 7.30-7.22 (m, 2H), 7.15-7.07 (m, 3H), 6.95-6.80 (m,5H), 4.50 (m, 1H), 4.18-3.90 (m, 6H), 3.09-2.90 (m, 1H), 2.83-2.58 (m,3H), 2.22-2.08 (m, 2H), 2.02-1.71 (m, 9H), 1.59 (m, 1H), 1.27-0.92 (m,2H).

MS (ESI+): m/z=590 (M+H⁺).

Example 193-({cis-[2-Carboxycyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid

The compound is prepared in analogy to the process described in Example11 from ethyl3-({cis-[2-(ethoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxy-butoxy)phenyl]propoxy}benzoate.

HPLC (method 2): R_(t): 5.16 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.59 (s, broad, 2H), 8.50-8.42 (m,2), 8.00 (dd, 1H), 7.30-7.18 (m, 3H), 7.13 (d, 2H), 6.95-6.82 (m, 5H),4.35 (m, 1H), 4.20 (m, 2H), 2.79-2.63 (m, 3H), 2.14 (m, 2H), 1.93-1.77(m, 6H), 1.70-1.53 (m, 3H), 1.46-1.33 (m, 3H).

MS (ESI+): m/z=590 (M+H⁺).

Example 201-(5-Carboxy-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoyl)-3-azetidine-carboxylicacid

The compound is prepared in analogy to the process described in Example11 from methyl1-(5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoyl)-3-azetidinecarboxylate.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.73 (s, broad, 2H), 7.95 (dd, 1H),7.82 (d, 1H), 7.27 (m, 2H), 7.16-7.11 (m, 3H), 6.93-6.83 (m, 5H), 4.21(t, 1H), 4.13-3.95 (m, 9H), 3.49-3.37 (m, 1H), 2.68 (t, 2H), 2.01(quint, 2H), 1.85 (m, 4H).

LC-MS (method 3): R_(t): 3.67 min.

MS (ESI+): m/z=548 (M+H⁺).

Example 214-{3-[4-(1,1′-Biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({cis-[2-carboxycyclohexyl]amino}carbonyl)benzoicacid

The compound is prepared in analogy to the process described in Example11 from ethyl4-{3-[4-(1,1′-Biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({cis-[2-(ethoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate.

HPLC (method 2): R_(t): 5.28 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.66 (s, broad, 2H), 8.56-8.43 (m,2H), 8.00 (dd, 1H), 7.72-7.62 (m, 4H), 7.56-7.31 (m, 5H), 7.27-7.12 (m,3H), 6.95 (d, 2H), 5.11 (s, 2H), 4.42-4.09 (m, 3H), 3.57 (m, 3H), 2.72(m, 3H), 2.25-2.03 (m, 2H), 1.97-1.29 (m, 5H).

MS (ESI+): m/z=608 (M+H⁺).

Example 22 Methyl4-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}-3-({[3-(methoxycarbonyl)-cyclohexyl]amino}carbonyl)benzoate

A solution of 17.88 g of (+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see. Example IX, method 2) and 19.9 g of1-(3-bromopropyl)-4-(3-cyclohexylpropoxy)benzene in 160 ml of anhydrousDMF is mixed with 20.85 g of cesium carbonate and heated at about 50 to60° C. for 3 hours. After cooling to room temperature, the mixture ispoured into 180 ml of 0.001 molar hydrochloric acid and extracted withethyl acetate. The organic phase is washed successively with water andsaturated brine, drying over h anhydrous sodium sulphate, filtration,evaporation. An oil is obtained and is mixed with a little ethyl acetateand cyclohexane. A solid precipitates out. The suspension is cooled inan ice bath for 1 hour. The solid is then filtered off with suction andwashed with a little cyclohexane. 26.0 g of a solid are obtained.

TLC: R_(f): 0.43 (cyclohexane/ethyl acetate 1:1).

HPLC (method 2): R_(t): 6.75 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.21 (d, 1H), 8.07 (d, 1H), 8.00 (dd,1H), 7.21 (d, 1H), 7.11 (d, 2H), 6.82 (d, 2H), 4.13 (pseudo-t, 3H), 3.89(t, 2H), 3.83 (s, 3H), 3.56 (s, 3H), 2.68 (pseudo-t, 3H), 2.07 (quint.,2H), 1.88-1.78 (m, 2H), 1.71-1.49 (m, 13H), 1.32-1.09 (m, 6H), 0.92-0.80(m, 2H).

MS (DCI, NH₃): m/z=594.3 (M+H⁺), 611.4 (M+NH₄ ⁺)

Example 233-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(3-cyclohexylpropoxy)phenyl]-propoxy}benzoicacid

A solution of 90.73 g of methyl4-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoatein 500 ml of THF and 500 ml of methanol is mixed with 300 ml of 2 molarsodium hydroxide solution and heated to 60° C. After one hour, theorganic solvents are removed as far as possible in a rotary evaporator.325 ml of 2 molar hydrochloric acid are added to the residue withstirring. A precipitate separates out during this and is filtered offwith suction and washed with water. The product is purified byrecrystallization from a mixture of 500 ml of acetone and 1000 ml ofwater. 77.5 g of product are obtained. m.p.: 160° C.

HPLC (method 1): R_(t): 5.61 min.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.48 (s broad, 2H), 8.21 (d, 1H),8.07 (d, 1H), 7.98 (dd, 1H), 7.18 (d, 1H), 7.12 (d, 2H), 6.82 (d, 2H),4.12 (pseudo-t, 3H), 3.88 (t, 2H), 2.70 (pseudo-t, 2H), 2.62 (m, 1H),2.07 (quint., 2H), 1.89-1.47 (m, 15H), 1.31-1.07 (m, 6H), 0.91-0.82 (m,2H).

MS (ESI+): m/z=566.5 (M+H⁺).

Example 24 Methyl4-(3-{4-[4-(cyclohexyloxy)butoxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-(3-bromopropyl)-4-[4-(cyclohexyloxy)butoxy]benzene.

TLC: R_(f): 0.46 (cyclohexane/ethyl acetate 1:1).

HPLC (method 2): R_(t): 6.08 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.22 (d, 1H), 8.08 (d, 1H), 8.00 (dd,1H), 7.21 (d, 1H), 7.11 (d, 2H), 6.82 (d, 2H), 4.13 (pseudo-t, 3H), 3.92(t, 2H), 3.82 (s, 3H), 3.57 (s, 3H), 3.42 (t, 2H), 3.21 (m, 1H), 2.69(pseudo-t, 3H), 2.07 (quint., 2H), 1.83-1.42 (m, 16H), 1.19 (m, 6H).

MS (DCI, NH₃): m/z=624 (M+H⁺), 641 (M+NH₄ ⁺).

Example 253-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[4-(cyclohexyloxy)butoxy]-phenyl}propoxy)benzoicacid

Preparation takes place in analogy to Example 23 from methyl4-(3-{4-[4-(cyclohexyloxy)butoxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]-amino}carbonyl)benzoate.

m.p.: 161-162° C.

HPLC (method 2): R_(t): 5.27 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.43 (s broad, 2H), 8.22 (d, 1H),8.05 (d, 1H), 7.98 (dd, 1H), 7.18 (d, 1H), 7.11 (d, 2H), 6.82 (d, 2H),4.13 (pseudo-t, 3H), 3.93 (t, 2H), 3.42 (t, 2H), 3.21 (m, 1H), 2.70(pseudo-t, 2H), 2.62 (m, 1H), 2.07 (quint., 2H), 1.91-1.42 (m, 17H),1.21 (m, 5H).

MS (ESI−): m/z=594 (M−H⁺)⁻.

Example 26 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxy-butoxy)phenyl]propoxy}benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-(3-bromopropyl)-4-[4-(phenoxy)butoxy]benzene.

TLC: R_(f): 0.35 (cyclohexane/ethyl acetate 1:1).

HPLC (method 2): R_(t): 5.80 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 8.20 (d, 1H), 8.12 (d, 1H), 8.01 (dd,1H), 7.31-7.19 (m, 3H), 7.12 (d, 2H), 6.90-6.83 (m, 5H), 4.13 (pseudo-t,3H), 3.99 (m, 4H), 3.83 (s, 3H), 3.57 (s, 3H), 2.70 (pseudo-t, 3H), 2.08(quint., 2H), 1.85 (m, 6H), 1.68-1.49 (m, 6H).

MS (ESI+): m/z=618 (M+H⁺), 640 (M+Na⁺).

Example 273-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid

Preparation takes place in analogy to Example 23 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}-benzoate.Since the product does not precipitate on acidification, it is extractedwith ethyl acetate, and the organic extract is dried over anhydroussodium sulphate. Filtration and evaporation result in the product.

HPLC (method 2): R_(t): 5.03 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.39 (s broad, 2H), 8.21 (d, 1H),8.05 (d, 1H), 7.98 (dd, 1H), 7.30-7.23 (dd, 2H), 7.18 (d, 1H), 7.12 (d,2H), 6.94-6.82 (m, 5H), 4.13 (pseudo-t, 3H), 4.00 (m, 4H), 2.70(pseudo-t, 2H), 2.62 (m, 1H), 2.07 (quint., 2H), 1.90-1.48 (m, 12H).

LC-MS (method 11): R_(t): 3.80 min, m/z (ESI+)=590 (M+H⁺).

Example 28 Ethyl4-{3-[4-(biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({[(1S,3R)-3-(methoxycarbonyl)cyclopentyl]amino}carbonyl)benzoate

Preparation takes place in analogy to Example 5 from2-{3-[4-(1,1′-biphenyl-4-yl-methoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoicacid and methyl (1R,3S)-3-aminocyclopentanecarboxylate hydrochloride.

HPLC (method 2): R_(t): 5.95 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.22 (d, 1H), 8.18 (d, 1H), 8.00 (dd,1H), 7.69-7.65 (m, 4H), 7.53-7.43 (m, 4H), 7.39-7.33 (m, 1H), 7.22 (d,1H), 7.14 (d, 2H), 6.94 (d, 2H), 5.11 (s, 2H), 4.30 (quart., 2H), 4.14(t, 2H), 3.55 (s, 3H), 2.88 (quint., 1H), 2.71 (pseudo-t, 2H), 2.32-2.22(m, 1H), 2.08 (quint., 2H), 1.99-1.82 (m, 3H), 1.78-1.57 (m, 2H), 1.31(t, 3H).

MS (ESI+): m/z=636 (M+H⁺).

Example 294-{3-[4-(Biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({[(1S,3R)-3-carboxycyclopentyl]amino}carbonyl)benzoicacid

Preparation takes place in analogy to Example 23 from ethyl4-{3-[4-(biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({[(1S,3R)-3-(methoxycarbonyl)cyclopentyl]amino}-carbonyl)benzoate.

HPLC (method 12): R_(t): 8.05 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.28 (s broad), 8.23 (d, 1H), 8.18(d, 1H), 7.98 (dd, 1H), 7.69-7.64 (m, 4H), 7.53-7.43 (m, 4H), 7.39-7.35(m, 1H), 7.18-7.13 (m, 3H), 6.94 (d, 2H), 5.11 (s, 2H), 4.31 (m, 1H),4.14 (t, 2H), 2.78 (quint., 1H), 2.70 (pseudo-t, 2H), 2.29-2.20 (m, 1H),2.08 (quint., 2H), 1.99-1.82 (m, 3H), 1.78-1.53 (m, 2H).

LC-MS (method 8): R_(t): 3.55 min, m/z (ESI+)=594 (M+H⁺).

Example 30 Methyl1-[2-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}-5-(methoxycarbonyl)-benzoyl]piperidine-4-carboxylate

A solution of 6.47 g of methyl1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate and 8.2g of 1-(3-bromopropyl)-4-(3-cyclohexylpropoxy)-benzene in 82 ml ofbutyronitrile is mixed with 4.18 g of potassium carbonate and heated toreflux for 15 hours. The reaction solution is then evaporated todryness, and the residue is taken up in water and extracted with ethylacetate. The organic phase is dried over sodium sulphate, filtered andconcentrated. The crude product is purified by suction filtrationthrough silica gel with cyclohexane/ethyl acetate 5:1 tocyclohexane/ethyl acetate 1:1 as mobile phase. 10.8 g of an oil areobtained.

TLC: R_(f): 0.36 (cyclohexane/ethyl acetate 1:1).

HPLC (method 2): R_(t): 6.07 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.97 (dd, 1H), 7.76 and 7.69 (each d,together 1H), 7.17 (d, 1H), 7.08 (d, 2H), 6.82 (d, 2H), 4.43 and 4.39(together 1H), 4.17-3.96 (m, 2H), 3.89 (t, 2H), 3.82 (s, 3H), 3.61 and3.57 (each s, together 3H), 3.11-2.88 (m, 2H), 2.63 (m, 3H), 1.96 (m,3H), 1.77-1.50 (m, 10H), 1.32-1.09 (m, 7H), 0.92-0.80 (m, 2H).

MS (ESI): m/z=580 (M+H⁺).

Example 311-(5-Carboxy-2-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}benzoyl)piperidine-4-carboxylicacid

Absolution of 10.4 g of methyl1-[2-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}-5-(methoxycarbonyl)benzoyl]piperidine-4-carboxylatein a mixture of 160 ml of THF and 160 ml of methanol is mixed with 160ml of 2 molar sodium hydroxide solution and stirred at a temperature of60° C. for 1 hour. The organic solvents are then removed as far aspossible in a rotary evaporator. 165 ml of 2 molar hydrochloric acid areadded to the remaining aqueous solution with stirring. A precipitateseparates out. Precipitation is completed by stirring at 0° C. Theprecipitate is filtered off with suction and washed with water. Thecrude product is purified by recrystallization from a solvent mixturecomposed of 250 ml of acetone and 200 ml of water. 8.7 g of a solid areobtained and are again heated to reflux in a mixture of 300 ml of waterand 100 ml of acetone for 6 hours. Cooling to 0° C., filtration, washingwith water and drying result in 8.6 g of a solid.

m.p.: 183.4-184.5° C.

HPLC (method 2): R_(t): 5.32 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.51 (s broad, 2H), 7.93 (dd, 1H),7.72 and 7.67 (each d, together 1H), 7.13 (d, 1H), 7.09 (d, 2H), 6.83and 6.90 (each d, together 2H), 4.43 and 4.38 (together 1H), 4.15-3.94(m, 2H), 3.88 (t, 2H), 3.11-2.88 (m, 2H), 2.62 (m, 2H), 2.54 (m, 1H),1.96 (m, 3H), 1.78-1.47 (m, 10H), 1.37-1.09 (m, 7H), 0.93-0.81 (m, 2H).

MS (ESI): m/z=552 (M+H⁺).

Example 32 Methyl4-(3-{4-[(4-isopropoxybenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-(3-bromopropyl)-4-[(4-isopropoxybenzyl)oxy]benzene.

TLC: R_(f): 0.43 (cyclohexane/ethyl acetate 1:1).

HPLC (method 2): R_(t): 5.69 min.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 8.21 (d, 1H), 8.10 (d broad, 1H), 8.01(dd, 1H), 7.32 (d, 2H), 7.22 (d, 1H), 7.13 (d, 2H), 6.91 (2 d, 4H), 4.95(s, 2H), 4.60 (sep, 1H), 4.13 (pseudo-t, 3H), 3.83 (s, 3H), 3.57 (s,3H), 2.69 (pseudo-t, 3H), 2.07 (pseudo-quint., 3H), 1.82 (m, 2H),1.68-1.47 (m, 6H), 1.24 (d, 6H).

MS (DCI, NH₃): m/z=618 (M+H⁺), 635 (M+NH₄ ⁺).

Example 333-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-isopropoxybenzyl)oxy]-phenyl}propoxy)benzoicacid

Preparation takes place in analogy to Example 23 from methyl4-(3-{4-[(4-isopropoxybenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]-amino}carbonyl)benzoate.

HPLC (method 2): R_(t): 4.97 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.47 (5 broad, 2H), 8.22 (d, 1H),8.07 (d broad, 1H), 7.98 (dd, 1H), 7.32 (d, 2H), 7.18 (d, 1H), 7.13 (d,2H), 6.91 (2 d, 4H), 4.96 (s, 2H), 4.59 (sep, 1H), 4.13 (pseudo-t, 3H),2.71 (pseudo-t, 2H), 2.63 (m, 1H), 2.08 (pseudo-quint., 2H), 1.91-1.47(m, 8H), 1.25 (d, 6H).

MS (ESI): m/z=590 (M+H⁺).

Example 34 Methyl4-(3-{4-[3-(5,5-dimethyl-1,3-dioxan-2-yl)propoxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate

A solution of 130 mg of methyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 85.9 mg of 2-(3-bromopropyl)-5,5-dimethyl-1,3-dioxane in 1 ml ofanhydrous DMF is mixed with 128.8 mg of caesium carbonate and stirred at100° C. for 15 hours. The reaction mixture is then loaded completelyonto an RP-HPLC system and chromatographed with a water/acetonitrilegradient. Evaporation of the product fractions results in 87.5 mg of asolid.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.37.

HPLC (method 2): R_(t): 5.54 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.22 (d, 1H), 8.08 (d broad, 1H), 8.01(dd, 1H), 7.22 (d, 1H), 7.11 (d, 2H), 6.83 (d, 2H), 4.48 (t, 1H), 4.14(pseudo-t, 3H), 3.93 (t, 2H), 3.83 (s, 3H), 3.58 (s, 3H), 3.52 (d, 2H),3.39 (d, 2H), 2.70 (m, 3H), 2.07 (quint, 2H), 1.84-1.72 (m, 4H),1.68-1.50 (m, 8H), 1.09 (s, 3H), 0.68 (s, 3H).

LC-MS (method 13): R_(t): 4.3 min. m/z (ESI+)=626 (M+H⁺).

Example 35 Methyl3-{[(3-carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[3-(5,5-dimethyl-1,3-dioxan-2-yl)propoxy]phenyl}propoxy)benzoate

A solution of 70.0 mg of methyl4-(3-{4-[3-(5,5-dimethyl-1,3-dioxan-2-yl)propoxy]-phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoatein 1 ml each of methanol, THF and 2 molar sodium hydroxide solution isstirred at a temperature of 60° C. for 2 hours. Then 1.1 ml of 2 molarhydrochloric acid are added, and the reaction mixture is left to standopen at room temperature for 15 hours. A precipitate separates out andis filtered off with suction and washed with water. If the precipitationis incomplete, extraction with ethyl acetate is possible. The organicextract is dried over anhydrous sodium sulphate and evaporated. 53.3 mgof a solid are obtained.

HPLC (method 2): R_(t): 4.86 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.52 (s broad, 2H), 8.21 (d, 1H),8.09 (d broad, 1H), 7.98 (dd, 1H), 7.19 (d, 1H), 7.13 (d, 2H), 6.83 (d,2H), 4.48 (t, 1H), 4.13 (pseudo-t, 3H), 3.92 (t, 2H), 3.52 (d, 2H), 3.39(d, 2H), 2.73-2.60 (m, 3H), 2.07 (quint, 2H), 1.87-1.47 (m, 12H), 1.09(s, 3H), 0.68 (s, 3H).

LC-MS (method 14): R_(t): 3.13 min, m/z (ESI+)=598 (M+H⁺).

Example 36 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-propoxybenzyl)oxy]phenyl}propoxy)benzoate

Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-propoxybenzyl)oxy]phenyl}propoxy)benzoateis prepared in analogy to the process described in Example 34 frommethyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 1-(chloromethyl)-4-propoxybenzene.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.39.

HPLC (method 2): R_(t): 5.67 min.

MS (ESI): m/z=618 (M+H⁺), 640 (M+Na⁺).

Example 373-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-propoxybenzyl)oxy]-phenyl}propoxy)benzoicacid

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-propoxybenzyl)oxy]-phenyl}propoxy)benzoicacid is prepared in analogy to the process described in Example 35 frommethyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-propoxybenzyl)oxy]phenyl}propoxy)benzoate.

HPLC (method 2): R_(t): 5.05 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.52 (s broad, 2H), 8.20 (d, 1H),8.09 (d broad, 1H), 7.98 (dd, 1H), 7.33 (d, 2H), 7.19 (d, 1H), 7.13 (d,2H), 6.92 (d, 2H), 6.91 (d, 2H), 4.96 (s, 2H), 4.12 (pseudo-t, 3H), 3.91(t, 2H), 2.73-2.58 (m, 3H), 2.06 (m, 2H), 1.87-1.48 (m, 10H), 0.97 (t,3H).

MS (ESI): m/z=588 (M−H⁺).

Example 38 Methyl4-[3-(4-{[4-(cyclopropylmethoxy)benzyl]oxy}phenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate

Methyl4-[3-(4-{[4-(cyclopropylmethoxy)benzyl]oxy}phenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateis prepared in analogy to the process described in Example 34 frommethyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 1-(chloromethyl)-4-(cyclopropylmethoxy)benzene.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.35.

HPLC (method 2): R_(t): 5.58 min.

MS (EST): m/z=630 (M+H⁺), 652 (M+Na⁺).

Example 393-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-[3-(4-{[4-(cyclopropylmethoxy)-benzyl]oxy}phenyl)propoxy]benzoicacid

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-[3-(4-{[4-(cyclopropylmethoxy)-benzyl]oxy}phenyl)propoxy]benzoicacid is prepared in analogy to the process described in Example 35 frommethyl4-[3-(4-{[4-(cyclopropylmethoxy)benzyl]-oxy}phenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-benzoate.

HPLC (method 2): R_(t): 4.99 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.52 (s broad, 2H), 8.20 (d, 1H),8.08 (d broad, 1H), 7.98 (dd, 1H), 7.33 (d, 2H), 7.18 (d, 1H), 7.13 (d,2H), 6.91 (2 d, 4H), 4.95 (s, 2H), 4.12 (pseudo-t, 3H), 3.80 (d, 2H),2.73-2.57 (m, 3H), 2.07 (m, 2H), 1.87-1.46 (m, 8H), 1.30-1.13 (m, 2H),0.57 (m, 2H), 0.32 (m, 2H).

MS (ESI): m/z=600 (M−H⁺).

Example 40 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-phenoxy-benzyl)oxy]phenyl}propoxy)benzoate

Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-phenoxybenzyl)oxy]phenyl}propoxy)benzoateis prepared in analogy to the process described in Example 34 frommethyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 1-(chloromethyl)-4-phenoxybenzene.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.36.

HPLC (method 2): R_(t): 5.86 min.

MS (ESI): m/z=652 (M+H⁺), 674 (M+Na⁺).

Example 413-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-phenoxybenzyl)oxy]-phenyl}propoxy)benzoicacid

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-phenoxybenzyl)oxy]-phenyl}propoxy)benzoicacid is prepared in analogy to the process described in Example 35 frommethyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-phenoxybenzyl)oxy]phenyl}propoxy)benzoate.

HPLC (method 2): R_(t): 5.19 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.45 (s broad, 2H), 8.21 (d, 1H),8.04 (d broad, 1H), 7.98 (dd, 1H), 7.40 (d, 1H), 7.38 (d, 2H), 7.21-6.88(m, 11H), 5.05 (s, 2H), 4.13 (pseudo-t, 3H), 2.07 (t, 2H), 2.61 (m, 1H),2.07 (m, 2H), 1.90-1.47 (m, 8H).

LC-MS (method 8): R_(t): 3.62 min, m/z (ESI+) 624 (M+H⁺).

Example 42 Methyl4-(3-{4-[(4-isobutoxybenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate

Methyl4-(3-{4-[(4-isobutoxybenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateis prepared in analogy to the process described in Example 34 frommethyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 1-(chloromethyl)-4-isobutoxybenzene.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.37.

HPLC (method 2): R_(t): 5.91 min.

MS (ESI): m/z=632 (M+H⁺), 654 (M+Na⁺).

Example 433-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-isobutoxybenzyl)-oxy]phenyl}propoxy)benzoicacid

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-isobutoxybenzyl)-oxy]phenyl}propoxy)benzoicacid is prepared in analogy to the process described in Example 35 frommethyl4-(3-{4-[(4-isobutoxybenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate.

HPLC (method 2): R_(t): 5.26 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.51 (s broad, 2H), 8.20 (d, 1H),8.08 (d broad, 1H), 7.98 (dd, 1H), 7.33 (d, 2H), 7.18 (d, 1H), 7.13 (d,2H), 6.91 (d, 2H), 6.90 (d, 2H), 4.97 (s, 2H), 4.12 (pseudo-t, 3H), 3.73(d, 2H), 2.73-2.58 (m, 3H), 2.10-1.90 (m, 3H), 1.86-1.68 (m, 3H),1.63-1.47 (m, 5H), 0.97 (d, 6H).

LC-MS (method 8): R_(t): 3.66 min m/z (ESI+)=604 (M+H⁺).

Example 44 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(5,6,7,8-tetrahydronaphthalen-2-ylmethoxy)phenyl]propoxy}benzoate

Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(5,6,7,8-tetrahydronaphthalen-2-ylmethoxy)phenyl]propoxy}benzoateis prepared in analogy to the process described in Example 34 frommethyl4-[3-(4-hydroxyphenyl)-propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 6-(chloromethyl)-1,2,3,4-tetrahydronaphthalene.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.47.

HPLC (method 2): R_(t): 5.97 min.

MS (ESI): m/z=614 (M+H⁺), 636 (M+Na⁺).

Example 453-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(5,6,7,8-tetrahydronaphthalen-2-ylmethoxy)phenyl]propoxy}benzoicacid

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(5,6,7,8-tetrahydronaphthalen-2-ylmethoxy)phenyl]propoxy}benzoicacid is prepared in analogy to the process described in, Example 35 frommethyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}-carbonyl)-4-{3-[4-(5,6,7,8-tetrahydronaphthalen-2-ylmethoxy)phenyl]-propoxy}benzoate.

HPLC (method 2): R_(t): 5.26 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.51 (s broad, 2H), 8.19 (d, 1H),8.08 (d broad, 1H), 7.98 (dd, 1H), 7.22-6.88 (m, 8H), 4.97 (pseudo-d,2H), 4.12 (pseudo-t, 3H), 2.72 (m, 7H), 2.08 (m, 2H), 1.87-1.48 (m,12H).

LC-MS (method 8): R_(t): 3.65 min, m/z (ESI+)=584 (M+H⁺).

Example 46 Methyl4-(3-{4-[(4-Cyclohexylbenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate

Methyl4-(3-{4-[(4-cyclohexylbenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateis prepared in analogy to the process described in Example 34 frommethyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 1-(chloromethyl)-4-cyclohexylbenzene.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.47.

HPLC (method 2): R_(t): 6.49 min.

LC-MS (method 13): R_(t): 4.9 min, m/z (ESI+)=642 (M+H⁺).

Example 473-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-cyclohexylbenzyl)oxy]-phenyl}propoxy)benzoicacid

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-cyclohexylbenzyl)oxy]-phenyl}propoxy)benzoicacid is prepared in analogy to the process described in Example 35 frommethyl4-(3-{4-[(4-cyclohexylbenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate.

HPLC (method 2): R_(t): 5.66 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.51 (s broad, 2H), 8.19 (d, 1H),8.08 (d broad, 1H), 7.97 (dd, 1H), 7.33 (d, 2H), 7.23-7.11 (m, 5H), 6.91(d, 2H), 5.01 (s, 2H), 4.12 (pseudo-t, 3H), 2.73-2.56 (m, 3H), 2.07 (m,2H), 1.87-1.14 (m, 19H).

LC-MS (method 14): R_(t): 3.57 min, m/z (ESI+)=614 (M+H⁺).

Example 48 Ethyl4-{3-[4-(biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({[(1R,3S)-3-(methoxycarbonyl)cyclopentyl]amino}carbonyl)benzoate

Preparation takes place in analogy to Example 5 from2-{3-[4-(1,1′-biphenyl-4-yl-methoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoicacid and methyl (1S,3R)-3-aminocyclopentanecarboxylate hydrochloride.

HPLC (method 2): R_(t): 6.02 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 8.23 (d broad, 1H), 8.21 (d, 1H), 8.00(dd, 1H), 7.69-7.65 (m, 4H), 7.53-7.43 (m, 4H), 7.39-7.33 (m, 1H), 7.22(d, 1H), 7.14 (d, 2H), 6.94 (d, 2H), 5.11 (s, 2H), 4.30 (quart., 2H),4.14 (t, 2H), 3.55 (s, 3H), 2.88 (quint., 1H), 2.71 (pseudo-t, 2H),2.32-2.22 (m, 1H), 2.08 (quint., 2H), 1.99-1.82 (m, 3H), 1.78-1.57 (m,2H), 1.31 (t, 3H).

MS (ESI+): m/z=636 (M+H⁺).

Example 494-{3-[4-(Biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({[(1R,3S)-3-carboxycyclopentyl]amino}carbonyl)benzoicacid

Preparation takes place in analogy to Example 23 from ethyl4-{3-[4-(biphenyl-4-ylmethoxy)phenyl]propoxy}-3-({[(1R,3S)-3-(methoxycarbonyl)cyclopentyl]amino}-carbonyl)benzoate.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 11 (s broad), 8.23 (d, 1H), 8.19 (d,1H), 7.98 (dd, 1H), 7.70-7.65 (m, 4H), 7.53-7.33 (m, 5H), 7.18-7.13 (m,3H), 6.94 (d, 2H), 5.11 (s, 2H), 4.30 (m, 1H), 4.22 (t, 2H), 2.78(quint., 1H), 2.70 (t, 2H), 2.23 (m, 1H), 2.08 (quint., 2H), 1.99-1.82(m, 3H), 1.73 (m, 1H), 1.59 (m, 1H).

LC-MS (method 8): R_(t): 3.56 min, m/z (ESI+)=594 (M+H⁺).

Example 50 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-[3-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)propoxy]benzoate

Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-[3-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)propoxy]benzoateis prepared in analogy to the process described in Example 34 frommethyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 1-(chloromethyl)-4-trifluoromethoxybenzene.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.36.

HPLC (method 2): R_(t): 6.62 min.

MS (ESI): m/z=644 (M+H⁺).

Example 513-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-[3-(4-{[4-(trifluoromethoxy)benzyl]-oxy}phenyl)propoxy]benzoicacid

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-[3-(4-{[4-(trifluoromethoxy)-benzyl]oxy}phenyl)propoxy]benzoicacid is prepared in analogy to the process described in Example 35 frommethyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-[3-(4-{[4-(trifluoromethoxy)benzyl]oxy}-phenyl)propoxy]benzoate.

HPLC (method 2): R_(t): 5.04 min.

¹H-NMR (200 MHz, DMSO-d₆, δ/ppm): 12.37 (s broad, 2H), 8.19 (d, 1H),8.08 (d broad, 1H), 7.98 (dd, 1H), 7.57 (d, 2H), 7.38 (d, 2H), 7.18 (d,2H), 7.17 (d, 2H), 6.93 (d, 2H), 5.01 (s, 2H), 4.12 (pseudo-t, 3H),2.74-2.56 (m, 3H), 2.08 (m, 2H), 1.87-1.43 (m, 8H).

MS (ESI): m/z 614 (M−H⁺).

Example 52 Methyl4-(3-{4-[3-(4-chlorophenyl)propoxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate

Methyl4-(3-{4-[3-(4-chlorophenyl)propoxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateis prepared in analogy to the process described in Example 34 frommethyl4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoateand 1-(3-bromopropyl)-4-chlorobenzene.

TLC (cyclohexane/ethyl acetate 1:1): R_(f): 0.44.

HPLC (method 2): R_(t): 5.90 min.

LC-MS (method 13): R_(t): 4.5 min, m/z (ESI+)=622 and 623 (M+H⁺).

Example 533-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[3-(4-chlorophenyl)propoxy]-phenyl}propoxy)benzoicacid

3-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[3-(4-chlorophenyl)propoxy]-phenyl}propoxy)benzoicacid is prepared in analogy to the process described in Example 35 frommethyl4-(3-{4-[3-(4-chlorophenyl)propoxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate.

HPLC (method 2): R_(t): 5.21 min.

LC-MS (method 14): R_(t): 3.37 min, m/z (ESI+)=594 and 596 (M+H⁺).

Example 54 Methyl4-{3-[4-(3-Cyclohexylpropoxy)phenyl]propoxy}-3-{[3-(2-ethoxy-2-oxo-ethyl)azetidin-1-yl]carbonyl}benzoate

Preparation takes place in analogy to the process described in Example22 from methyl3-{[3-(2-ethoxy-2-oxoethyl)azetidin-1-yl]carbonyl}-4-hydroxybenzoate and1-(3-bromopropyl)-4-(3-cyclohexylpropoxy)benzene.

HPLC (method 5): R_(t): 5.83 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 7.97 (dd, 1H), 7.83 (d, 1H), 7.20-7.09(m, 3H), 6.83 (d, 2H), 4.19-3.94 (m, 6H), 3.94-3.86 (m, 2H), 3.82 (s,3H), 3.75-3.67 (m, 1H), 3.63-3.54 (m, 1H), 2.95-2.82 (m, 1H), 2.74-2.62(m, 4H), 2.05-1.96 (m, 2H), 1.75-1.55 (m, 7H), 1.33-1.08 (m, 9H),0.96-0.78 (m, 2H).

MS (ESI+): m/z=580 (M+H⁺).

Example 553-{[3-(Carboxymethyl)azetidin-1-yl]carbonyl}-4-{3-[4-(3-cyclohexylpropoxy)-phenyl]propoxy}benzoicacid

Preparation takes place in analogy to Example 11 from methyl4-{3-[4-(3-cyclohexylpropoxy)phenyl]-propoxy}-3-{[3-(2-ethoxy-2-oxoethyl)azetidin-1-yl]carbonyl}benzoate.

HPLC (method 5): R_(t): 5.05 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.48 (s, broad, 2H), 7.94 (dd, 1H),7.81 (d, 1H), 7.13 (pseudo-d, 3H), 6.82 (d, 2H), 4.19-4.04 (m, 3H), 3.98(t, 1H), 3.89 (t, 2H), 3.70 (q, 1H), 3.57 (q, 1H), 2.93-2.77 (m, 1H),2.75-2.54 (m, 4H), 2.09-1.95 (m, 2H), 1.76-1.55 (m, 7H), 1.35-1.04 (m,6H), 0.97-0.79 (m, 2H).

MS (ESI+): m/z=538 (M+H⁺).

Example 56 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(5-phenoxy-pentyl)phenyl]propoxy}benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-(3-iodopropyl)-4-(5-phenoxypentyl)benzene.

HPLC (method 5): R_(t): 5.57 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.87 (d, 1H), 8.09 (dd, 1H), 7.86 (d,1H), 7.30-7.22 (m, 2H), 7.14-7.06 (m, 4H), 6.98-6.84 (m, 4H), 4.43-4.34(m, 1H), 4.19 (t, 2H), 3.95 (t, 2H), 3.89 (s, 3H), 3.65 (s, 3H), 2.81(t, 2H), 2.65-2.54 (m, 3H), 2.30-2.19 (m, 2H), 2.01-1.94 (m, 2H),1.87-1.62 (m, 9H), 1.56-1.47 (m, 3H).

LC-MS (method 9): R_(t): 3.19 min. m/z (EI+)=615.

Example 573-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{3-[4-(5-phenoxypentyl)phenyl]-propoxy}benzoicacid

Preparation takes place in analogy to Example 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{3-[4-(5-phenoxypentyl)phenyl]-propoxy}benzoate.

HPLC (method 5): R_(t): 4.94 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.92 (d, 1H), 8.12 (dd, 1H), 7.86 (d,1H), 7.29-7.22 (m, 2H), 7.12-7.08 (m, 4H), 6.98-6.85 (m, 4H), 4.48-4.34(m, 1H), 4.18 (t, 2H), 3.94 (t, 2H), 2.82 (t, 2H); 2.72-2.56 (m, 3H),2.30-1.23 (m, 18H).

LC-MS (method 9): R_(t): 2.75 min, m/z (EI+)=587.

Example 58 Ethyl3-{[3-(2-ethoxy-2-oxoethyl)azetidin-1-yl]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoate

Preparation takes place in analogy to Example IX, method 3, from3-(2-ethoxy-2-oxoethyl)azetidinium chloride and5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)-phenyl]propoxy}benzoicacid.

HPLC (method 5): R_(t): 5.19 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.07-8.00 (m, 2H), 7.31-7.23 (m, 2H),7.10 (d, 2H), 6.96-6.81 (m, 6H), 4.40-4.30 (m, 4H), 4.17-3.98 (m, 8H),3.90-3.83 (m, 1H), 3.70-3.62 (m, 1H), 3.05-2.93 (m, 1H), 2.79-2.70 (m,2H), 2.70-2.55 (m, 2H), 2.17-2.07 (m, 2H), 2.00-1.93 (m, 4H), 1.37 (t,3H), 1.22 (t, 3H).

MS (ESI+): m/z=618 (M+H⁺).

Example 593-{[3-(Carboxymethyl)azetidin-1-yl]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoicacid

Preparation takes place in analogy to Example 11 from ethyl3-{[3-(2-ethoxy-2-oxoethyl)azetidin-1-yl]carbonyl}-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}-benzoate.

HPLC (method 5): R_(t): 4.39 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.48 (s, broad, 2H), 7.94 (dd, 1H),7.81 (d, 1H), 7.31-7.24 (m, 2H), 7.14 (pseudo-d, 3H), 6.95-6.82 (m, 5H),4.18-3.95 (m, 8H), 3.69 (dd, 1H), 3.62-3.56 (m, 1H), 2.92-2.80 (m, 1H),2.69 (t, 2H), 2.61-2.55 (m, 2H), 2.08-1.96 (m, 2H), 1.89-1.81 (m, 4H).

LC-MS (method 6): R_(t): 2.32 min, m/z (EI+)=561.

Example 60 Methyl4-{2-[4-(biphenyl-4-ylmethoxy)phenoxy]ethoxy}-3-({[3-(methoxycarbonyl)-cyclohexyl]amino}carbonyl)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and4-{[4-(2-bromoethoxy)phenoxy]methyl}biphenyl.

HPLC (method 5): R_(t): 5.22 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 8.90 (d, 1H), 8.15 (dd, 1H), 7.91 (d,1H), 7.65-7.34 (m, 8H), 7.08-6.82 (m, 6H), 5.06 (s, 2H), 4.53-4.45 (m,2H), 4.42-4.32 (m, 3H), 3.91 (s, 3H), 3.61 (s, 3H), 2.52-2.38 (m, 1H),1.84 (t, 2H), 1.76-1.24 (m, 6H).

MS (ESI+): m/z=638 (M+H⁺).

Example 614-{2-[4-(Biphenyl-4-ylmethoxy)phenoxy]ethoxy}-3-{[(3-carboxycyclohexyl)amino]-carbonyl}benzoic acid

Preparation takes place in analogy to Example 11 from methyl4-{2-[4-(biphenyl-4-ylmethoxy)phenoxy]ethoxy}-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-benzoate.

HPLC (method 5): R_(t):4.66 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.39 (d, 1H), 8.06-7.99 (m, 2H),7.69-7.65 (m, 4H), 7.54-7.44 (m, 4H), 7.39-7.27 (m, 2H), 7.00-6.90 (m,4H), 5.10 (s, 2H), 4.55-4.49 (m, 2H), 4.37-4.33 (m, 2H), 4.14-4.04 (m,1H), 2.47-2.38 (m, 1H), 1.80-1.22 (m, 8H).

LC-MS (method 9): R_(t): 2.53 min, m/z (EI+)=609.

Example 62 Methyl4-{3-[4-(2-biphenyl-4-ylethyl)phenyl]propoxy}-3-({[3-(methoxycarbonyl)-cyclohexyl]amino}carbonyl)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and4-{2-[4-(3-iodopropyl)phenyl]ethyl}biphenyl.

HPLC (method 5): R_(t): 5.64 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.87 (d, 1H), 8.09 (dd, 1H), 7.85 (d,1H), 7.61-7.55 (m, 2H), 7.54-7.48 (m, 2H), 7.46-7.39 (m, 3H), 7.36-7.22(m, 2H), 7.18-7.08 (m, 4H), 6.96 (d, 1H), 4.44-4.30 (m, 1H), 4.19 (t,2H), 3.89 (s, 3H), 3.65 (s, 3H), 2.83 (t, 2H), 2.69-2.55 (m, 1H),2.31-2.19 (m, 2H), 2.02-1.95 (m, 2H), 1.81-1.62 (m, 5H), 1.40-1.22 (m,5H).

LC-MS (method 9): R_(t): 3.24 min, m/z (EI+)=633.

Example 634-{3-[4-(2-Biphenyl-4-ylethyl)phenyl]propoxy}-3-{[(3-carboxycyclohexyl)amino]-carbonyl}benzoicacid

Preparation takes place in analogy to Example 11 from methyl4-{3-[4-(2-biphenyl-4-ylethyl)phenyl]propoxy}-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-benzoate.

HPLC (method 5): R_(t): 5.03 min.

LC-MS (method 9): R_(t): 2.82 min, m/z (EI+)=605.

Example 64 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{2-[4-(4-phenoxy-butoxy)phenoxy]ethoxy}benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-(2-bromoethoxy)-4-(4-phenoxybutoxy)benzene.

HPLC (method 5): R_(t): 5.11 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 8.90 (d, 1H), 8.15 (dd, 1H), 7.92 (d,1H), 7.33-7.22 (m, 2H), 7.07-6.81 (m, 8H), 4.55-4.46 (m, 2H), 4.42-4.32(m, 2H), 4.07-3.95 (m, 4H), 3.90 (s, 3H), 3.62 (s, 3H), 2.53-2.36 (m,1H), 2.04-1.78 (m, 6H), 1.70-1.25 (m, 7H).

MS (ESI+): m/z=620 (M+H⁺).

Example 653-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-{2-[4-(4-phenoxybutoxy)phenoxy]-ethoxy}benzoicacid

Preparation takes place in analogy to Example 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-{2-[4-(4-phenoxybutoxy)-phenoxy]ethoxy}benzoate.

HPLC (method 5): R_(t):4.52 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.45 (s, broad, 2H); 7.39 (d, 1H),8.07-7.98 (m, 2H), 7.34-7.22 (m, 3H), 6.95-6.83 (m, 7H), 4.56-4.49 (m,2H), 4.37-4.32 (m, 2H), 4.15-3.93 (m, 5H), 2.48-2.39 (m, 1H), 1.89-1.22(m, 12H).

LC-MS (method 9): R_(t): 2.42 min, m/z (EI+)=591.

Example 66 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(2-{4-[(1Z)-5-phenoxypent-1-en-1-yl]phenoxy}ethoxy)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-(2-iodoethoxy)-4-[(1Z)-5-phenoxypent-1-en-1-yl]benzene.

HPLC (method 5): R_(t): 5.33 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.90 (d, 1H), 8.14 (dd, 1H), 7.85 (d,1H), 7.29-7.21 (m, 4H), 7.04 (d, 1H), 6.94-6.83 (m, 5H), 6.39 (d, 1H),5.64 (dt, 1H), 4.56-4.50 (m, 2H), 4.44-4.30 (m, 2H), 4.39-4.30 (m, 1H),3.99 (t, 2H), 3.91 (s, 3H), 3.61 (s, 3H), 2.54-2.32 (m, 3H), 2.10-1.7(m, 5H), 1.48-1.23 (m, 5H).

LC-MS (method 14): R_(t): 3.63 min, m/z (EI+)=615.

Example 673-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(2-{4-[(1Z)-5-phenoxypent-1-en-1-yl]phenoxy}ethoxy)benzoicacid

Preparation takes place in analogy to Example 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(2-{4-[(1Z)-5-phenoxypent-1-en-1-yl]phenoxy}ethoxy)benzoate.

HPLC (method 5): R_(t): 4.67 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.88 (s, 1H), 8.10 (d, 1H), 7.88 (d,1H), 7.30-7.16 (m, 3H), 7.01-6.81 (m, 7H), 6.36 (d, 1H), 5.65-5.54 (m,1H), 4.52-4.28 (m, 5H), 4.01-3.91 (m, 2H), 2.54-2.42 (m, 2H), 2.03-1.18(m, 11H).

LC-MS (method 9): R_(t): 2.54 min, m/z (EI+)=587.

Example 68 Methyl1-[2-{2-[4-(Biphenyl-4-ylmethoxy)phenoxy]ethoxy}-5-(methoxycarbonyl)-benzoyl]piperidine-4-carboxylate

Preparation takes place in analogy to Example 22 from methyl1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]piperidine-4-carboxylate and4-{[4-(2-bromoethoxy)-phenoxy]methyl}biphenyl.

HPLC (method 5): R_(t): 5.02 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.05 (d, 1H), 7.95 (dd, 1H), 7.64-7.55(m, 4H), 7.52-7.40 (m, 4H), 7.38-7.33 (m, 1H), 7.03-6.90 (m, 3H),6.88-6.81 (m, 2H), 5.06 (s, 2H), 4.54-4.18 (m, 5H), 3.89 (s, 3H), 3.68and 3.57 (s, together 3H), 3.53-3.37 (m, 1H), 3.15-2.88 (m, 2H),2.56-2.39 (m, 1H), 2.01-1.88 (m, 1H), 1.87-1.60 (m, 3H).

LC-MS (method 9): R_(t): 2.79 min, m/z (EI+)=623.

Example 691-(2-{2-[4-(Biphenyl-4-ylmethoxy)phenoxy]ethoxy}-5-carboxybenzoyl)piperidine-4-carboxylicacid

Preparation takes place in analogy to Example 11 from methyl1-[2-{2-[4-(biphenyl-4-ylmethoxy)phenoxy]ethoxy}-5-(methoxycarbonyl)benzoyl]piperidine-4-carboxylate.

HPLC (method 5): R_(t): 4.42 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 12.52 (s, broad, 2H), 7.96 (dd, 1H);7.75-7.64 (m, 5H), 7.56-7.43 (m, 4H), 7.40-7.33 (m, 1H), 7.25 (d, 1H),7.01-6.86 (m, 4H), 5.08 (d, 2H), 4.48-4.38 (m, 2H), 4.34-4.21 (m, 3H),3.15-2.75 (m, 2H), 2.48-2.37 (m, 1H), 1.91-1.26 (m, 4H).

Example 70 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-({3-[4-(4-phenoxy-butoxy)phenyl]prop-2-yn-1-yl}oxy)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-(3-bromoprop-1-yn-1-yl)-4-(4-phenoxy-butoxy)benzene.

HPLC (method 5): R_(t): 5.23 min.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.9 (d, 1H), 8.15 (dd, 1H), 7.98 (d,1H), 7.38 (d, 2H), 7.31-7.25 (m, 2H), 7.10 (d, 1H), 6.94 (t, 1H), 6.89(d, 2H), 6.84 (d, 2H), 5.09 (s, 2H), 4.47-4.40 (m, 1H), 4.08-4.01 (m,4H), 3.91 (s, 3H), 3.62 (s, 3H), 2.64-2.57 (m, 1H), 2.11-1.95 (m, 5H),1.88-1.80 (m, 1H), 1.72-1.49 (m, 6H).

MS (CI+): m/z=614 (M+H⁺).

Example 713-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-({3-[4-(4-phenoxybutoxy)phenyl]-prop-2-yn-1-yl}oxy)benzoicacid

Preparation takes place in analogy to Example 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-({3-[4-(4-phenoxybutoxy)-phenyl]prop-2-yn-1-yl}oxy)benzoate.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.55 (s, broad, 2H), 8.23 (d, 1H),8.13 (d, 1H), 8.04 (dd, 1H), 7.40 (d, 2H), 7.34 (d, 1H), 7.26 (dd, 2H),6.98-6.88 (m, 5H), 5.22 (s, 2H), 4.18-3.97 (m, 5H), 2.62-2.55 (m, 1H),1.92-1.43 (m, 12H).

LC-MS (method 6): R_(t): 2.59 min, m/z (EI+)=585.

Example 72 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-phenoxy-but-2-yn-1-yl)oxy]phenyl}propoxy)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-(3-bromopropyl)-4-[(4-phenoxybut-2-yn-1-yl)oxy]benzene.

HPLC (method 5): R_(t): 5.00 min.

¹H-NMR (200 MHz, CDCl₃, δ/ppm): 8.87 (d, 1H), 8.09 (dd, 1H), 7.86 (d,1H), 7.35-7.21 (m, 1H), 7.10 (d, 2H), 7.04-6.81 (m, 7H), 4.71 (s, 4H),4.46-4.32 (m, 1H), 4.18 (t, 2H), 3.89 (s, 3H), 3.65 (s, 3H), 2.70 (t,2H), 2.72-2.52 (m, 2H), 2.32-2.14 (m, 2H), 1.98 (t, 2H), 1.88-1.45 (m,5H).

LC-MS (method 6): R_(t): 3.14 min, m/z (EI+)=613.

Example 733-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(4-phenoxybut-2-yn-1-yl)oxy]-phenyl}propoxy)benzoicacid

Preparation takes place in analogy to Example 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-phenoxybut-2-yn-1-yl)oxy]phenyl}propoxy)benzoate.

HPLC (method 5): R_(t): 4.39 min.

¹H-NMR (400 MHz, CDCl₃, δ/ppm): 8.68 (d, 1H), 8.06 (dd, 1H), 7.94 (d,1H), 7.27 (t, 2H), 7.10 (d, 2H), 7.03 (d, 1H), 6.98-6.82 (m, 5H), 4.74(d, 4H), 4.38-4.29 (m, 1H), 4.23-4.15 (m, 2H), 2.79 (t, 2H), 2.27-2.18(m, 2H), 2.03-1.85 (m, 2H), 1.84-1.52 (m, 7H).

LC-MS (method 7): R_(t): 2.39 min, m/z (EI+)=585.

Example 74 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(1Z)-5-phenoxypent-1-en-1-yl]phenyl}propoxy)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and(4Z)-5-[4-(3-bromopropyl)phenyl]pent-4-en-1-yl phenyl ether.

HPLC (method 5): R_(t): 5.42 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.87 (d, 1H), 8.08 (dd, 1H), 7.84 (d,1H), 7.30-7.20 (m, 4H), 7.13 (d, 2H), 6.97-6.84 (m, 4H), 6.43 (d, 1H),5.68 (dq, 1H), 4.43-4.34 (m, 1H), 4.19 (t, 2H), 4.02-3.94 (m, 2H), 3.89(s, 3H), 3.65 (s, 3H), 3.42 (t, 2H), 2.84 (t, 2H), 2.64-2.54 (m, 1H),2.53 (dq, 2H), 2.33-2.20 (m, 2H), 2.04-1.60 (m, 8H).

LC-MS (method 7): R_(t): 3.40 min, m/z (EI+)=613.

Example 753-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(1Z)-5-phenoxypent-1-en-1-yl]phenyl}propoxy)benzoicacid

Preparation takes place in analogy to Example 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(1Z)-5-phenoxypent-1-en-1-yl]phenyl}propoxy)benzoate.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.91 (d, 1H), 8.11 (dd, 1H), 7.84 (d,1H), 7.30-7.18 (m, 4H), 7.13 (d, 2H), 6.97-6.83 (m, 4H), 6.43 (d, 1H),5.67 (dq, 1H), 4.48-4.35 (m, 1H), 4.19 (t, 2H), 3.98 (t, 2H), 2.84 (t,2H), 2.73-2.61 (m, 1H), 2.51 (dq, 2H), 2.33-2.18 (m, 2H), 2.15-2.04 (m,1H), 2.02-1.52 (m, 9H).

LC-MS (method 7): R_(t): 2.68 min, m/z (EI+)=585.

Example 76 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(1E)-5-phenoxypent-1-en-1-yl]phenyl}propoxy)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and(4E)-5-[4-(3-bromopropyl)phenyl]pent-4-en-1-yl phenyl ether.

HPLC (method 5): R_(t): 5.44 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.86 (d, 1H), 8.09 (d, 1H), 7.84 (d,1H), 7.32-7.23 (m, 4H), 7.11 (d, 2H), 6.97-6.86 (m, 4H), 6.40 (d, 1H),6.28-6.16 (m, 1H), 4.42-4.35 (m, 1H), 4.18 (t, 2H), 4.02 (t, 2H), 3.89(s, 3H), 3.65 (s, 3H), 2.83 (t, 2H), 2.73-2.54 (m, 2H), 2.44-2.35 (m,2H) 2.30-2.17 (m, 2H), 2.03-1.96 (m, 4H), 1.85-1.22 (m, 5H).

LC-MS (method 7): R_(t): 3.22 min, m/z (EI+)=613.

Example 773-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-(3-{4-[(1E)-5-phenoxypent-1-en-1-yl]-phenyl}propoxy)benzoicacid

Preparation takes place in analogy to Example 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(1E)-5-phenoxypent-1-en-1-yl]phenyl}propoxy)benzoate.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.91 (d, 1H), 8.12 (dd, 1H), 7.84 (d,1H), 7.32-7.20 (m, 5H), 7.11 (d, 1H), 6.98-6.86 (m, 4H), 6.40 (d, 1H),6.22 (dt, 1H), 4.48-4.36 (m, 1H), 4.17 (t, 2H), 4.00 (t, 2H), 2.86 (t,2H), 2.74-2.63 (m, 1H), 2.44-2.33 (m, 2H) 2.30-2.18 (m, 2H), 2.17-2.03(m, 1H), 2.02-1.22 (m, 9H).

LC-MS (method 7): R_(t): 2.72 min, m/z (EI+)=585.

Example 78 Methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-({(2E)-3-[4-(4-phenoxybutoxy)phenyl]prop-2-en-1-yl}oxy)benzoate

Preparation takes place in analogy to Example 22 from the(+)-B-enantiomer of methyl4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate(see Example IX, method 2) and1-[(1E)-3-bromoprop-1-en-1-yl]-4-(4-phenoxybutoxy)benzene.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.94 (d, 1H), 8.17 (dd, 1H), 8.08 (d,1H), 7.37 (d, 2H), 7.33-7.24 (m, 2H), 7.07 (d, 1H), 6.96-6.84 (m, 5H),6.78 (d, 1H), 6.35 (dt, 1H), 4.83 (d, 2H), 4.48-4.39 (m, 1H), 4.08-4.00(m, 4H), 3.90 (s, 3H), 3.60 (s, 3H), 2.53-2.40 (m, 1H), 2.10-1.93 (m,5H), 1.83-1.37 (m, 7H).

MS (ESI+): m/z=638 (M+Na⁺)

Example 793-{[(3-Carboxycyclohexyl)amino]carbonyl}-4-({(2E)-3-[4-(4-phenoxybutoxy)-phenyl]prop-2-en-1-yl}oxy)benzoicacid

Preparation takes place in analogy to Example 11 from methyl3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-({(2E)-3-[4-(4-phenoxybutoxy)-phenyl]prop-2-en-1-yl}oxy)benzoate.

HPLC (method 5): R_(t): 4.66 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.95 (d, 1H), 8.17 (dd, 1H), 8.08 (d,1H), 7.36 (d, 2H), 7.32-7.22 (m, 2H), 7.07 (d, 1H), 6.96-6.74 (m, 6H),6.34 (dt, 1H), 4.83 (d, 2H), 4.50-4.40 (m, 1H), 4.08-3.96 (m, 4H),2.58-2.46 (m, 1H), 2.08-1.46 (m, 12H).

LC-MS (method 7): R_(t): 2.76 min, m/z (EI+)=587.

Example 80 Ethyl3-[({[2-(methoxycarbonyl)cyclohexyl]methyl}amino)carbonyl]-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate

Preparation takes place in analogy to Example IX, method 3, from[2-(methoxycarbonyl)cyclohexyl]methanammonium bromide and5-(ethoxy-carbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoicacid.

HPLC (method 5): R_(t): 5.62 min.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 8.86 (d, 1H), 8.09 (dd, 1H), 7.93 (t,1H), 7.31-7.25 (m, 2H), 7.10 (d, 2H), 6.97-6.82 (m, 6H), 4.35 (q, 2H),4.16 (t, 2H), 4.07-3.98 (m, 4H), 3.70-3.59 (m, 1H), 3.58 (s, 3H),3.41-3.30 (m, 1H), 2.80-2.68 (m, 3H), 2.27-2.11 (m, 3H), 2.01-1.83 (m,5H), 1:74-1.55 (m, 5H), 1.44-1.33 (m, 2H), 1.37 (t, 3H).

MS (ESI+): m/z=646 (M+H⁺).

Example 813-({[(2-Carboxycyclohexyl)methyl]amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)-phenyl]propoxy}benzoicacid

Preparation takes place in analogy to Example 11 from ethyl3-[({[2-(methoxycarbonyl)cyclohexyl]methyl}amino)carbonyl]-4-{3-[4-(4-phenoxybutoxy)phenyl]-propoxy}benzoate.

HPLC (method 5): R_(t): 4.64 min.

¹H-NMR (300 MHz, DMSO-d₆, δ/ppm): 8.23 (d, 1H), 8.12 (t, 1H), 7.98 (dd,1H), 7.31-7.25 (m, 2H), 7.21-7.10 (m, 3H), 6.95-9.82 (m, 5H), 4.14 (t,2H), 4.05-3.96 (m 4H), 3.6-3.2 (m, 2H, underneath water signal), 2.68(t, 2H), 2.62-2.56 (m, 1H), 2.12-1.93 (m, 3H), 1.88-1.82 (n, 4H),1.82-1.12 (m, 8H).

MS (ESI−): m/z=602 (M−H⁺)

The following compounds are additionally prepared in analogy toprocesses described in the above examples. (Unless indicated otherwise,all derivatives containing the

fragment are prepared from the (+) Benantiomer of the compound ofExample IX, method 2.)

Molecular MS or LC- Ex. mass HPLC HPLC R_(t) MS No. Structure [g/mol]method [min] (method) 82

703 2 6.04 4.7 min,704 (13) 83

675 2 5.40 3.47 min,675 (14) 84

661 2 6.06 662 (ESI) 85

633 2 5.39 3.71 min,633 (8) 86

601 2 5.87 602 (ESI) 87

573 2 5.24 572 (ESI) 88

665 2 5.82 666 (ESI) 89

637 2 5.17 3.62 min,637 (8) 90

615 2 6.17 616 (ESI) 91

587 1 5.46 586 (ESI) 92

654 2 5.56 655 (ESI) 93

626 2 4.91 3.46 min,626 (8) 94

591 2 5.65 4.34 min,592/614 (8) 95

563 2 5.0 3.24 min,563 (14) 96

601 2 5.76 602 (DCI) 97

573 2 5.03 572 (ESI) 98

615 2 6.01 616 (ESI) 99

587 1 5.29 586 (ESI) 100

601 2 5.86 602 (DCI) 101

573 2 5.12 572 (ESI) 102

617 2 5.58 4.3 min,617 (13) 103

589 2 4.93 3.18 min,589 (14) 104

608 2 5.72 608 (ESI) 105

580 2 5.03 3.25 min,579 (14) 106

601 2 5.7 602 (ESI) 107

573 2 5.04 572 (ESI) 108

664 2 5.67 664 (ESI) 109

636 2 5.01 3.49 min,635 (8) 110

617 2 5.81 618 (ESI) 111

575 12 7.7 3.44 min,575 (8) 112

603 2 5.41 604 (DCI) 113

575 2 4.7 574 (ESI) 114

627 2 6.15 628 (DCI) 115

599 2 5.35 598 (ESI) 116

609 2 5.73 610 (DCI) 117

581 2 4.9 580 (ESI) 118

646 2 5.36 647 (DCI) 119

618 2 5.15 3.29 min,619 (8) 120

553 2 5.85 554 (ESI) 121

525 2 5.11 524 (ESI) 122

567 2 6.08 568 (ESI) 123

539 2 5.31 538 (ESI) 124

567 2 6.18 568 (ESI) 125

539 2 5.45 538 (ESI) 126

581 2 6.50 582 (ESI) 127

553 2 5.66 552 (ESI) 128

595 2 7.08 5.1 min,595 (13) 129

567 2 5.86 3.64 min,567 (14) 130

609 — — 3.08 min,610 (6) 131

567 — — 2.60 min,568 (7) 132

538 2 5.63 638 (ESI) 133

610 2 4.94 3.46 min,609 (8) 134

617 2 5.8 618 (ESI) 135

575 — — 3.45 min,575 (8) 136

615 2 6.13 616 (ESI) 137

587 1 5.43 586 (ESI) 138

619 2 5.59 620 (DCI) 139

591 2 4.89 590 (ESI) 140

579 2 6.30 580 (ESI) 141

551 1 5.35 550 (ESI) 142

581 2 6.49 582 (DCI) 143

553 2 5.51 552 (ESI) 144

607 — — 608 (ESI) 145

579 — — 3.24 min,579 (7) 146

617 2 5.60 618 (ESI) 147

589 2 4.9 2.52 min,589 (9) 148

617 2 5.69 618 (DCI) 149

589 2 4.99 588 (ESI) 150

565 2 5.83 566 (DCI) 151

537 2 5.06 538 (ESI) 152

607 2 6.60 608 (ESI) 153

579 2 5.69 578 (ESI) 154

667 2 4.32 456 (ESI) 155

639 2 4.74 3.6 min,639 (8) 156

607 1 6.47 608 (ESI) 157

565 2 5.45 564 (ESI) 158

617 2 5.69 618 (ESI) 159

589 2 5.06 588 (ESI) 160

629 2 5.49 630 (ESI) 161

601 2 4.80 602 (ESI) 162

631 — — — 163

603 — — — 164

573 2 5.45 574 (ESI) 165

545 2 4.77 3.27 min,545 (8) 166

647 2 5.82 648 (DCI) 167

619 2 5.1 618 (ESI) 168

589 2 5.3 590 (DCI) 169

561 2 4.62 560 (ESI) 170

595 2 5.57 596 (DCI) 171

567 2 4.8 566 (ESI) 172

607 2 6.63 608 (ESI) 173

579 2 5.74 578 (ESI) 174

587 2 5.56 588 (ESI) 175

559 2 4.89 560 (ESI) 176

601 2 5.27 602 (ESI) 177

573 2 4.67 574 (ESI) 178

617 1 5.69 618 (ESI) 179

589 1 4.99 3.96 min,589 (8) 180

645 4 5.78 646 (ESI) 181

589 2 4.89 588 (ESI) 182

581 2 5.26 582 (DCI) 183

553 1 4.52 554 (ESI) 184

635 2 5.37 636 (ESI) 185

607 2 4.66 3.22 min,607 (8) 186

580 2 5.39 580 (DCI) 187

552 2 4.71 550 (ESI) 188

580 2 5.41 580 (ESI) 189

552 2 4.6 550 (ESI) 190

611 2 5.27 612 (DCI) 191

583 2 4.56 582 (ESI) 192

725 4 6.13 726 (ESI) 193

607 2 5.02 608 (EI+) 194

631 2 5.78 632 (ESI) 195

589 2 4.83 590 (ESI) 196

649 2 5.88 650 (ESI) 197

593 2 5.05 3.92 min,594 (8, EI+) 198

631 2 5.73 632 (ESI) 199

575 2 4.90 3.82 min,576 (8, EI+) 200

649 1 5.92 650 (ESI) 201

593 1 5.01 594(DCI, NH₃) 202

631 1 5.77 632 (ESI) 203

575 1 4.88 576(DCI, NH₃)B. Assessment of the Physiological ActivityAbbreviations:DMEM Dulbecco's modified Eagle mediumFCS Fetal calf serumHEPES 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid1. Cellular In Vitro Test to Determine the CysLT2 Activity

A recombinant cell line is used to identify antagonists of the humancysteinyl-leukotriene 2 receptor (CysLT2R) and to quantify the activityof the substances described herein. The cell is originally derived froma hamster ovary epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC:American Type Culture Collection, Manassas, Va. 20108, USA). The testcell line constitutively expresses the calcium-sensitive photoproteinaequorin which, after reconstitution with the cofactor coelenterazine,emits light when the cytoplasmic calcium concentration is increased(Rizzuto R, Simpson A W, Brini M, Pozzan T.; Nature 358 (1992) 325-327).The cell is additionally stably transfected with the human CysLT2receptor (Heise et.al., JBC 275 (2000) 30531-30536). The resultingCysLT2R test cell responds to stimulation of the recombinant CysLT2receptor (agonists: leukotriene D4 (LTD4) and leukotriene C4 (LTC4))with an intracellular release of calcium ions, which can be quantifiedthrough the resulting aequorin luminescence with a suitable luminometer(Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 17(1996) 235-237). Preincubation with antagonists of the CysLT2 receptorreduces the calcium release induced by the agonists LTD4 and LTC4 andthus the measured amount of light.

Test procedure: The cells are plated out two days before the test inculture medium (DMEM/F12 with Glutamax, Gibco Cat.# 61965-026; 10% FCS,Gibco Cat.# 10270-106; 1.4 mM sodium pyruvate, Gibco Cat.# 11360-039;1.8 mM sodium bicarbonate, Gibco Cat.# 25080-060; 10 mM HEPES, GibcoCat.# 15290-026; now belongs to Invitrogen GmbH, 76131 Karlsruhe) in384- (or 1536-)well microtitre plates and kept in a cell incubator (96%humidity, 5% V/V CO₂, 37° C.). On the day of the test, the culturemedium is replaced by Tyrode solution (in mM: 140 NaCl, 5 KCl, 1 MgCl₂,2 CaCl₂; 20 glucose, 20 HEPES) which additionally contains the cofactorcoelenterazine (50 μM), and the microtitre plate is then incubated for afurther 3-4 hours. 15 minutes after the test substances have beentransferred into the wells of the microtitre plate, the resulting lightsignal is measured after addition of the LTD4 (3×10⁻⁸ M) in theluminometer. The results are shown in Table 1.

2. Cellular In Vitro Test to Determine the CysLT1 Activity

A recombinant cell line is used to identify antagonists of the humancysteinyl-leukotriene 1 receptor (CysLT1R) and to quantify the activityof the substances described herein. The cell is originally derived froma hamster ovary epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC:American Type Culture Collection, Manassas, Va. 20108, USA). The testcell line constitutively expresses the calcium-sensitive photoproteinaequorin which, after reconstitution with the cofactor coelenterazine,emits light when the cytoplasmic calcium concentration is increased(Rizzuto R, Simpson A W, Brini M, Pozzan T.; Nature 358 (1992) 325-327).The cell is additionally stably transfected with the human CysLT1receptor (Lynch et al., Nature 399 (1999) 789-793). The resultingCysLT1R test cell responds to stimulation of the recombinant CysLT1receptor (agonist: leukotriene D4 (LTD4)) with an intracellular releaseof calcium ions, which can be quantified through the resulting aequorinluminescence with a suitable luminometer (Milligan G, Marshall F, ReesS. Trends in Pharmacological Sciences 17 (1996) 235-237). Preincubationwith antagonists of the CysLT1 receptor reduces the calcium releaseinduced by the agonist LTD4 and thus the measured amount of light.

Test procedure: The cells are plated out two days before the test inculture medium (DMEM/F12 with Glutamax, Gibco Cat.# 61965-026; 10% FCS,Gibco Cat.# 10270-106; 1.4 mM sodium pyruvate, Gibco Cat.# 11360-039;1.8 mM sodium bicarbonate, Gibco Cat.# 25080-060; 10 mM HEPES, GibcoCat.# 15290-026; now belongs to Invitrogen GmbH, 76131 Karlsruhe) in384- (or 1536-)well microtitre plates and kept in a cell incubator (96%humidity, 5% V/V CO₂, 37° C.). On the day of the test, the culturemedium is replaced by Tyrode solution (in mM: 140 NaCl, 5 KCl, 1 MgCl₂,2 CaCl₂, 20 glucose, 20 HEPES) which additionally contains the cofactorcoelenterazine (50 μM), and the microtitre plate is then incubated for afurther 3-4 hours. 15 minutes after the test substances have beentransferred into the wells of the microtitre plate, the resulting lightsignal is measured after addition of the LTD4 (3×10⁻⁹M) in theluminometer. The results are shown in Table 1.

TABLE 1 CysLT1 activity/CysLT2 activity comparison Example No. CysLT1:IC₅₀ (nM) CysLT2: IC₅₀ (nM) 11 >10000 35 23 2000 5 25 >10000 6 31 250014 33 >10000 153. In Vivo Test to Detect the Cardiovascular Effect: Langendorff GuineaPig Heart

The heart is removed after opening the chest cavity of anaesthetizedguinea pigs and is introduced into a conventional Langendorff apparatus.The coronary arteries are subjected to a constant volume (10 ml/min)perfusion, and the perfusion pressure arising thereby is recorded via anappropriate pressure transducer. A decrease in the perfusion pressure inthis arrangement corresponds to a relaxation of the coronary arteries.At the same time, the pressure developed by the heart during eachcontraction (the left ventricular pressure) is measured by a balloonintroduced into the left ventricle, and a further pressure transducer.The rate at which the isolated heart beats is found by calculation fromthe number of contractions per unit time.

To detect the effect of CysLT2 receptor antagonists, the perfusion withthe agonist LTC4 (10⁻⁸ M) is started 15 minutes before addition ofincreasing concentrations of the test substance (10⁻⁸ to 10⁻⁶ M).

TABLE 2 Change in the perfusion pressure in isolated guinea pig heartsafter addition of LTC4 in absence and presence of various concentratonsof test substances Perfusion pressure relative to control without LTC4[%] LTC4 LTC4 LTC4 LTC4 (10⁻⁸M) (10⁻⁸M) + (10⁻⁸M) + (10⁻⁸M) + Ex. notest test sub. test sub. test sub. No. sub. (10⁻⁸M) (10⁻⁷M) (10⁻⁶M) 11127 125 112 108 23 134 133 127 111 25 131 128 123 111 31 130 128 123 11233 127 122 121 108

TABLE 3 Change in the left ventricular pressure in isolated guinea pighearts after addition of LTC4 in absence and presence of variousconcentratons of test substances Left ventricular pressure relative tocontrol without LTC4 [%] LTC4 LTC4 LTC4 LTC4 (10⁻⁸M) (10⁻⁸M) + (10⁻⁸M) +(10⁻⁸M) + Ex. no test test sub. test sub. test sub. No. sub. (10⁻⁸M)(10⁻⁷M) (10⁻⁶M) 11 47 44 60 79 23 59 72 84 97 25 46 55 71 89 31 54 67 8187 33 44 44 57 84

C. Exemplary Embodiments of Pharmaceutical Compositions

The compounds of the invention can be converted into pharmaceuticalpreparations in the following way:

Tablets:

Composition:

100 mg of the compound of Example 11, 50 mg of lactose (monohydrate), 50mg of microcrystalline cellulose, 10 mg of polyvinylpyrrolidone (PVP)(from BASF, Ludwigshafen, Germany), 10 mg of crosslinked Nacarboxymethylcellulose and 2 mg of magnesium stearate.

Tablet weight 222 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of active ingredient, lactose and cellulose is granulatedwith a 5% strength solution (m/m) of the PVP in water. The granules aredried and then mixed with the crosslinked Na carboxymethylcellulose andthe magnesium stearate for 5 minutes. This mixture is compressed in aconventional tablet press (see above for tablet format). As a guideline,a compressive force of 15 kN is used for the compression.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound of Example 11, 1000 mg of ethanol (96%), 400 mgof xanthan gum (from FMC, Pennsylvania, USA) and 97.6 g of water. 10 gof oral suspension correspond to a single dose of 100 mg of the compoundof the invention.

Production:

The xanthan gum is suspended in ethanol, and the active ingredient isadded to the suspension. The water is added while stirring. The mixtureis stirred for about 6 h until the xanthan gum has finished swelling.

Solution which can be Administered Orally:

Composition

500 mg of the compound of Example 11, 2.5 g of polysorbate and 97 g ofpoly-ethylene glycol 400.20 g of oral solution correspond to a singledose of 100 mg of the compound of the invention.

Production

The active ingredient is suspended by stirring in the mixture ofpolyethylene glycol and polysorbate. The stirring process is continueduntil the active ingredient has completely dissolved.

Solution which can be Administered Intravenously:

The active ingredient is dissolved in a concentration below thesaturation solubility in a physiologically tolerated solvent (seeExamples). The solution is sterilized by filtration and dispensed intosterile and pyrogen-free injection/infusion containers.

Composition I:

100 mg of the compound of Example 11, 15 g of polyethylene glycol 400and 250 g of a 2% strength aqueous sodium bicarbonate solution forinjections.

Production:

The compound of Example 11 is dissolved together with polyethyleneglycol 400 by stirring in the 2% strength aqueous sodium bicarbonatesolution. The solution is sterilized by filtration (pore diameter 0.22μm) and dispensed under aseptic conditions into heat-sterilized infusionbottles. The latter are closed with infusion stoppers and crimped caps.

Composition II:

100 mg of the compound of Example 11 and 250 ml of an aqueous solutionof 0.31 g of anhydrous citric acid and 5.66 g of sodium monohydrogenphosphate dihydrate.

Production:

The compound of Example 11 is dissolved by stirring in the aqueoussolution. The solution is sterilized by filtration and dispensed underaseptic conditions into sterile and pyrogen-free injection/infusioncontainers.

Composition III:

100 mg of the compound of Example 11 and 250 ml of an aqueous solutionof 0.044 g of anhydrous citric acid, 0.81 g of sodium monohydrogenphosphate dihydrate and 1.87 g of sodium chloride.

Production:

The compound of Example 11 is dissolved by stirring in the aqueoussolution. The solution is sterilized by filtration and dispensed underaseptic conditions into sterile and pyrogen-free injection/infusioncontainers.

1. A compound of the formula

in which A is a 6-membered nitrogen-containing saturated heterocyclewhich is bonded via the nitrogen atom to the keto group and whichoptionally has a carbonyl group adjacent to a nitrogen atom, m 0,1 or 2,n is 1, 2, 3 or 4, R¹ is hydrogen or (C₁-C₆)-alkyl, R² is hydrogen or(C₁-C₆)-alkyl, X is a bond, —CH═CH—, —C≡C— or O, Y is O, *—NH—C(═O)— orNH, in which * is the point of linkage to the phenyl ring, and Z islocated in the position meta or para to the substituent X and is either(C₆-C₁₀)-alkoxy which may comprise 1 or 2 further oxygen atoms in thechain, or a radical

 in which G is a bond, O or S, L is (C₁-C₆)-alkanediyl,(C₃-C₆)-alkenediyl or (C₃-C₆)-alkynediyl, M is a bond, O or S, R⁴ is(C₆-C₁₀)-aryl, biphenylyl, phenoxyphenyl, benzyloxyphenyl,(E)-phenylvinylphenyl, 2-phenylethyiphenyl, tetrahydronaphthyl, benzyl,heteroaryl, 5- to 10-membered heterocyclyl, (C₃-C₇)-cycloalkyl or(C₃-C₇)-cycloalkylmethyl, where aryl, biphenylyl, phenoxyphenyl,benzyloxyphenyl, (E)-phenylvinylphenyl, 2-phenylethyiphenyl,tetrahydronaphthyl, benzyl, heteroaryl, heterocyclyl, cycloalkyl andcycloalkylmethyl in turn may be substituted up to three timesindependently of one another by halogen, cyano, nitro, trifluoromethyl,trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₂-C₆)-alkenyl,(C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkylmethoxy, (C₅-C₇)-cyclo-alkenyl,(C₃-C₇)-cycloalkoxy or (C₅-C₇)-cycloalkenyloxy, and * is the point oflinkage to the phenyl ring, or a salt thereof.
 2. The compound of claim1, in which A is a 6-membered nitrogen-containing saturated heterocyclewhich is bonded via the nitrogen atom to the keto group, m is 0 or 1, nis 1, 2 or 3, R¹ is hydrogen, R² is hydrogen, X is a bond or O, Y is Oor *—NH—C(═O)—, in which * is the point of linkage to the phenyl ring,and Z is located in the position meta or para to the substituent X andis either (C₇-C₉)-alkoxy, which may comprise 1 further oxygen atom inthe chain, or a radical

 in which G is a bond or O, L is (C₁-C₆)-alkanediyl or(C₃-C₆)-alkenediyl, M is a bond, O or S, R⁴ is phenyl, naphthyl,biphenylyl, phenoxyphenyl, benzyloxyphenyl, (E)-phenylvinylphenyl,2-phenylethylphenyl, tetrahydronaphthyl, benzyl, 1,3-dioxanyl,1,4-dioxanyl, dimethyl- 1,3-dioxanyl, tetrahydro-2H-pyranyl,(C₃-C₇)-cycloalkyl or (C₃-C₇)-cycloalkylmethyl, where phenyl, naphthyl,biphenylyl, phenoxyphenyl, benzyloxyphenyl, (E)-phenylvinylphenyl,2-phenylethylphenyl, tetrahydronaphthyl, benzyl, cycloalkyl andcycloalkylmethyl in turn may be substituted up to three timesindependently of one another by halogen, cyano, nitro, trifluoromethyl,trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkylmethoxy or (C₃-C₇)-cycloalkoxy, and * is the point oflinkage to the phenyl ring, or a salt thereof.
 3. The compound of claim1, in which A—[CH₂]_(m)—CO₂R¹ is a radical

in which * is the point of linkage to the keto group, n is 3, R² ishydrogen, X is a bond, Y is O, and Z is located in the position pam tothe substituent X and is either n-octyloxy, n-heptyloxy, or a radical

 in which * is the point of linkage to the phenyl ring, or a radical

 in which G is O, L is methanediyl, n-propanediyl or n-butanediyl, M isa bond or O, R⁴ is phenyl, 4-biphenylyl, 4-phenoxyphenyl,4-benzyloxyphenyl, 1,2,3,4-tetrahydronaphth-6-yl,5,5-dimethyl-1,3-dioxan-2-yl or cyclohexyl, where phenyl in turn may besubstituted once by halogen, trifluoromethoxy, (C₃-C₄)-alkyl,(C₃-C₄)-alkoxy, cyclopentyl, cyclohexyl or (C₃-C₆)-cycloalkylmethoxy,and * is the point of linkage to the phenyl ring, or a salt thereof. 4.The compound of claim 1, in which A—[CH₂]_(m)—CO₂R¹ is a radical

in which * is the point of linkage to the keto group, n is 3, R² ishydrogen, X is a bond, Y is O, and Z is located in the position para tothe substituent X, and is either n-octyloxy, n-heptyloxy, or a radical

 in which * is the point of linkage to the phenyl ring, or a radical*—O—CH₂R⁴, in which R⁴ is phenyl, 4-biphenylyl, 4-phenoxyphenyl,4-benzyloxyphenyl or 1,2,3,4-tetrahydronaphth-6-yl, where phenyl in turnmay be substituted once by trifluoromethoxy, n-propyl, n-butyl,tert-butyl, n-propyloxy, isopropyloxy, isobutyloxy, cyclohexyl orcyclopropylmethoxy, and * is the point of linkage to the phenyl ring, ora radical *—O—CH₂—CH₂—CH₂—R⁴, in which R⁴ is 4-chlorophenyl,5,5-dimethyl-1,3-dioxan-2-yl or cyclohexyl, and * is the point oflinkage to the phenyl ring, or a radical *—O—CH₂—CH₂—CH₂—CH₂—O—R⁴, inwhich R⁴ is phenyl or cyclohexyl, and * is the point of linkage to thephenyl ring, or a salt thereof.
 5. The compound of claim 1, in whichA—[CH₂]_(m)—CO₂R¹ is a radical

in which * is the point of linkage to the keto group, n is 3, R² ishydrogen, X is a bond, Y is O, and Z is located in the position para tothe substituent X and is a radical

in which * is the point of linkage to the phenyl ring, or a saltthereof.
 6. The compound of claim 1, wherein the compound is1-(5-carboxy-2-{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}benzoyl)piperidine-4-carboxylicacid, or a salt thereof.
 7. A process for preparing a compound of claim1, comprising either [A] reacting a compound of the formula (II)

in which R² is (C₁-C₆)-alkyl and n, X, Y and Z have the meaningindicated in claim 1, with a compound of the formula (III)

in which R¹ is (C₁-C₆)-alkyl, and m and A have the meaning indicated inclaim 1, or [B1] reacting a compound of the formula (IVa)

in which Q¹ is a leaving group and n, X and Z have the meaning indicatedin claim 1, with a compound of the formula (Va)

in which R¹ and R² are (C₁-C₆)-alkyl, and A and m have the meaningindicated in claim 1, or [B2] reacting a compound of the formula (IVb)

in which Q² is an acid chloride group, and n, X and Z have the meaningindicated in claim 1, with a compound of the formula (Vb)

in which R¹ and R² are (C₁-C₆)-alkyl, and A and m have the meaningindicated in claim 1, or [B3] reacting a compound of the formula (IVa)

in which Q¹ is a leaving group and n, X and Z have the meaning indicatedin claim 1, with a compound of the formula (Vb)

in which R¹ and R² are (C₁-C₆)-alkyl, and A and m have the meaningindicated in claim 1, or [C] reacting a compound of the formula (XII)

in which R¹ and R² are (C₁-C₆)-alkyl, and n, m, X, Y and A have themeaning indicated in claim 1, with a compound of the formula (XIII)R⁴-M-L-Q³ (XIII), in which Q³ is a leaving group and R⁴, M and L havethe meaning indicated in claim 1, or [D] hydrolysing the two estergroups in the compound prepared by process step [A], [B1], [B2], [B3] or[C].
 8. A pharmaceutical composition comprising at least one compound ofclaim 1 and at least one excipient.
 9. A pharmaceutical compositioncomprising at least one compound of claim 1 and at least one furtheractive ingredient.